WO2019104201A1 - Agonistes et antagonistes à petites molécules de l'activité de nr2f6 chez des non-humains - Google Patents

Agonistes et antagonistes à petites molécules de l'activité de nr2f6 chez des non-humains Download PDF

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WO2019104201A1
WO2019104201A1 PCT/US2018/062290 US2018062290W WO2019104201A1 WO 2019104201 A1 WO2019104201 A1 WO 2019104201A1 US 2018062290 W US2018062290 W US 2018062290W WO 2019104201 A1 WO2019104201 A1 WO 2019104201A1
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compound
compounds
nr2f6
cell
activity
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Harry M. LANDER
David R. Koos
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Zander Therapeutics Inc
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Zander Therapeutics Inc
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Priority claimed from US15/820,334 external-priority patent/US20190054118A1/en
Priority claimed from US15/820,324 external-priority patent/US11324719B2/en
Priority claimed from US16/008,526 external-priority patent/US11377442B2/en
Priority claimed from US16/008,631 external-priority patent/US10472351B2/en
Application filed by Zander Therapeutics Inc filed Critical Zander Therapeutics Inc
Publication of WO2019104201A1 publication Critical patent/WO2019104201A1/fr
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/46—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom
    • C07D333/48—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings substituted on the ring sulfur atom by oxygen atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
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    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/12—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 3 and unsubstituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present technology relates to agonists and antagonists of nuclear receptor activity, specifically to the modulation of NR2F6 activity and NR2F6 utilizing compounds, and the immune modulation and modulation of cancer stem cell activity through administration of compounds described herein.
  • T cells of the immune system are known to recognize and interact with specific molecules through receptors (e.g., a T cell receptor in complex with a CD3 dimer) which, upon recognition or interaction with these molecules, result in the activation of the T cell to perform various immune activities.
  • receptors e.g., a T cell receptor in complex with a CD3 dimer
  • Innate immune cells are cells of the immune system that are known to be activated by one or more agents (e.g., allergens, chemicals produced upon injury (e.g., opioids and alcohols), polymyxins, crosslinked IgE, crosslinked complement proteins, cytokines produced by T cells or other immune cells (e.g., interferon-g), DAMPs, or PAMPs) that activate downstream signaling pathway(s) in the innate immune cell and result in the activation of one or more immune activities of the innate immune cell.
  • agents e.g., allergens, chemicals produced upon injury (e.g., opioids and alcohols), polymyxins, crosslinked IgE, crosslinked complement proteins, cytokines produced by T cells or other immune cells (e.g., interferon-g), DAMPs, or PAMPs
  • Both T cells and innate immune cells play a role in a mammal's immune defense.
  • the immune activities of an innate immune cell can protect a mammal against infectious diseases.
  • the immune activities of a T cell can protect a mammal against, for example, infectious diseases and cancer.
  • Adoptive cell therapy is a method of treatment that includes harvesting one or more different types of immune cells from a mammal, culturing and/or manipulating the harvested immune cells ex vivo, and administering the cultured and/or manipulated immune cells back to the mammal.
  • the manipulating of a harvested immune cell ex vivo can include introducing a recombinant nucleic acid into the immune cell.
  • Molecularly targeted therapeutics represent a new approach to discovering anti cancer drugs. Using this approach, small molecules are designed to inhibit directly the very oncogenetic proteins that are mutated or overexpressed in specific tumor cell types. By targeting specific molecular defects or conditions found within tumor cells, this approach can yield therapies tailored to each tumor’s genetic makeup.
  • a complementary strategy involves searching for genotype- selective anti-tumor agents that become lethal to tumor cells only in the presence of specific oncoproteins or only in the absence of specific tumor oppressors.
  • genotype-selective compounds might target oncoproteins directly, or target other critical proteins involved in oncoprotein-linked signaling networks.
  • the immune system is comprised of activatory and inhibitory mechanisms that can allow for control of immune responses and subsequent inhibition of responses after clearance of the immune target.
  • the central event stimulating immune responses is the antigen-specific activation of naive CD4 + T cells subsequent to binding antigen presenting cell MHC containing antigenic peptide.
  • the CD4 + T cell also known as the“helper T cell,” helps to coordinate the activation of the adaptive immune response, playing a role in the stimulation of cytotoxic CD8+ T cells, whose role includes destroying host cells affected by cancer, viruses, and intracellular bacteria, as well as stimulating B cell maturation to eventual plasma cell differentiation.
  • Antibodies can be critical molecules in clearance of extracellular pathogens such as various bacteria and parasites.
  • naive CD4 + T cells require two distinct signals to proliferate and differentiate into the armed effector cells that mediate adaptive immunity.
  • Signal 1 of this two-signal model is antigen-specific and is generated by interaction of the TCR with antigenic peptide presented in context with MHC II antigens. This results in transduction of TCR intracellular signals leading to production of IU-2 and T cell activation.
  • Signal 2 is referred to as a“costimulatory” signal because, while essential, it does not necessarily induce any functional response in T cells.
  • CD28 delivers a costimulatory signal upon interaction with CD80 or CD86 present on B cells, macrophages, or dendritic cells. Activation of the TCR in the presence of costimulatory signals leads to T cell clonal expansion and initiation of effector functions such as IL-2 production.
  • immune checkpoints For cancer, immune inhibitory mechanisms, termed“immune checkpoints,” are prematurely activated in order for the tumor to escape immune attack.
  • CTLA-4 is related to CD28, however instead of activating T cells in a co-stimulatory manner, it leads to inhibition or co-inhibition of T cells.
  • Nuclear receptor subfamily 2 group F, member 6 (NR2F6), also known as nuclear orphan receptor Ear2, is an orphan member of the nuclear receptor (NR) superfamily of ligand- activated receptors, which exhibit a common modular structure and are involved in various homeostatic functions, but also play a role in oncogenesis and cancer propagation.
  • NR nuclear receptor
  • studies have shown that members of the NR family regulate development, reproduction, and metabolism of lipids, drugs and energy. The importance of this family of proteins in metabolic disease is exemplified by NR ligands used in the clinic or under exploratory development for the treatment of diabetes mellitus, dyslipidemia, hypercholesterolemia, or other metabolic abnormalities.
  • the present disclosure is directed to, in certain embodiments, methods of using small molecule compounds as immune modulators; as well as to compounds, solid forms and compositions thereof that are immune modulators and that exhibit desirable characteristics thereof; as well as to methods of making the compounds, solid forms and composition thereof.
  • the present technology is directed compounds discussed and described herein, which compounds have been found to modulate the immune system.
  • These compounds can include any of the following:
  • Q2 A can be any of the following: C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • n can be an integer 1, 2, 3, 4, 5 or 6.
  • any of R, RA, RB, R1-R8, X, Q, Ql, Q2, or A can be any of the following: Me, OMe, Br, N, H, Cl, F or N0 2 .
  • any of R, RA, RB, R1-R8, X, Q, Ql, Q2, or A can be any of the following: 4-Me, 4-OMe, 4-Br, 4-t-Bu, 3,4-di-Me, 4-C1, 3,4-di- Cl, 3-C1-4-F, 2-F, 3 -Cl, 3-CH 3 -4-F, a thiazole, an isothiazole or a dithiolane.
  • any of Rl and R2 can have the values shown in any of the
  • FIGS. 1A-1F for example, FIGS. 1A-1F, FIGS. 3A-3F, FIGS. 4A-4L, FIGS. 5A and 5B, FIGS. 6A-6F, FIGS. 7A-70, FIGS. 8A-8M, FIGS. 9A-9J, FIGS. 10A-10J or FIGS. 11A-11G
  • the present technology is directed a compound having a structure of any of the following, or a pharmaceutically acceptable salt thereof:
  • the present technology is directed to a novel compound, any solid form thereof, and any formulation or composition thereof, that is useful as agonists or antagonists of nuclear receptor activity, specifically to the modulation of NR2F6 activity and NR2F6 utilizing compounds.
  • the present technology is directed to methods of modulating the immune system or modulating cancer cell activity using compounds that alter activity of NR2F6.
  • the present technology is directed to methods of
  • reprogramming the immune cells in a patient to attack tumors or other invasive cells.
  • Such “reprogramming” can include: (a) extraction of an amount of a patient’s cellular material (including, but not limited to: blood, which itself includes blood serum, plasma red blood cells, white blood cells and platelets), (b) isolating specific immune cells from the cellular material; (c) inhibiting or activating the NR2F6 target in the extracted immune cells; and (d) re-administering the immune cells (for example, by injection) to the patient’s body.
  • cellular material including, but not limited to: blood, which itself includes blood serum, plasma red blood cells, white blood cells and platelets
  • the present technology is directed to methods treating or reducing the effect of an autoimmune response, reaction, disease or disorder, the method comprising any of the steps discussed herein, or activating the NR2F6 target in isolated immune cells by binding them with a compound according to the present technology.
  • the present technology is directed to methods of shrinking (reducing the size of) a tumor, increasing or decreasing the activity of a cell, initiating or inducing an immune response, destroying a cancer cell, reducing the effect of a disease, alleviating a symptom of a disease, treating a disorder, as well as methods of inducing a cell in a patient’s body to do any of these, the method comprising administering a compound herein to a tumor, contacting a compound herein with a cell, or any other steps discussed herein.
  • these methods can comprise: comprising the steps of:
  • the present technology is directed to methods of treating or reducing the effect of a reaction, disease or disorder, the method comprising activating the NR2F6 target in immune cells by contacting them with a compound herein.
  • the present technology is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein, with a pharmaceutically acceptable carrier or excipient.
  • non-human means any living thing other than a human, for example, a mammal.
  • FIGS. 1A-1F show certain compounds that have been found to be effective for the purposes of the present technology.
  • FIG. 2A shows a certain compound that has been found to be effective for the purposes of the present technology.
  • FIG. 2B shows different domains, or portions of a base compound, that were substituted with different moieties to ascertain whether these made a difference in the activity of such compound.
  • FIG. 3A shows a certain compound that has been found to be effective for the purposes of the present technology.
  • FIGS. 3B-3F show various additional compounds formed from substitution of different moieties.
  • FIGS. 4A-4L show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIGS. 5A and 5B show additional embodiments of compounds, along with (in the case of FIG. 5A) different values of moieties Rl and R2.
  • FIGS. 6A-6F show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIGS. 7A-70 show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIGS. 8A-8M show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIGS. 9A-9J show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIGS. 10A-10J show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIGS. 11A-11G show additional compounds that were found to be useful in accordance with the embodiments herein.
  • FIG. 12 shows a certain compound that has been found to be effective for the purposes of the present technology; and different domains, or portions of a base compound, that were substituted with different moieties to ascertain whether these made a difference in the activity of such compound.
  • FIG. 13A shows a certain compound that has been found to be effective for the purposes of the present technology.
  • FIGS. 13B-13H show various additional compounds formed from substitution of different moieties.
  • FIG. 14A shows a certain compound that has been found to be effective for the purposes of the present technology.
  • FIGS. 14B-14D show various additional compounds formed from substitution of different moieties.
  • FIGS. 15A-15G show additional compounds that were found to be useful in accordance with the embodiments herein
  • FIGS. 16A and 16B show charts of cytokines release by hPBMC and cytotox for
  • FIGS. 17A and 17B show analogues and other related compounds to Compound
  • FIGS. 18A and 18B show charts of cytokines release by hPBMC and cytotox for
  • Compound 18 For cytokines release and cytotox on hPBMCs compound was tested at 1.25, 2.5, 5, 10, 25 and 50 uM in duplicates. For cytotox on HEK293, HEK293 pGL4 and HEK293 NR2F6 (full length) compound was tested from 50 uM with dilution step 3.16 in duplicates. Human PBMC were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) w/o compounds.
  • FIGS. 19A and 19B show the results of Dog’s PBMC ELISA and cytotoxicity experiments. All compounds were tested at 5, 10, 25 and 50 uM in duplicates on activated by 10 ng/mL PMA + 500 ng/mL ionomycin dogs PBMC (1 x 106 cells/mL). Cell culture supemates were removed and frozen for further ELISA analysis and remained cells were analyzed. Compounds without cytotox were chosen for cytokine release inhibition analysis. Compound Z92 was also analyzed at 5uM and lOuM.
  • FIGS. 20A and 20B show results of cytokines release by hPBMC and cytotox for
  • Compound Z95 For cytokines release and cytotox on hPBMCs compound was tested at 1.25, 2.5, 5, 10, 25 and 50 uM in duplicates. For cytotox on HEK293, HEK293 pGL4 and HEK293 NR2F6 (full length) compound was tested from 50 uM with dilution step 3.16 in duplicates. Human PBMC were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) without compounds.
  • FIGS. 21A-21D show human and dog results of a cytokine release experiment - parent compound for dogs and human PBMC, for Compound D28. All compounds were tested at 5, 10, 25 and 50 uM in duplicates. Dog PBMC (1 x 106 cells/mL) were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) without (0%) PMA + ionomycin activation. [0052] FIGS. 22A and 22B show results of cytokines release by hPBMC and cytotox for
  • Compound Z17 For cytokines release and cytotox on hPBMCs compound was tested at 1.25, 2.5, 5, 10, 25 and 50 uM in duplicates. For cytotox on HEK293, HEK293 pGL4 and HEK293 NR2F6 (full length) compound was tested from 50 uM with dilution step 3.16 in duplicates. Human PBMC were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) without compounds.
  • FIGS. 23A and 23B show results of cytokines release by hPBMC and cytotox for
  • Compound Z33 For cytokines release and cytotox on hPBMCs compound was tested at 1.25, 2.5, 5, 10, 25 and 50 uM in duplicates. For cytotox on HEK293, HEK293 pGL4 and HEK293 NR2F6 (full length) compound was tested from 50 uM with dilution step 3.16 in duplicates. Human PBMC were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) without compounds.
  • FIG. 24 shows results of a cytokines release by hPBMC for Compound E56.
  • FIGS. 25A and 25B show results of cytokines release by hPBMC and cytotox for
  • Compound Z96 For cytokines release and cytotox on hPBMCs compound was tested at 1.25, 2.5, 5, 10, 25 and 50 uM in duplicates. For cytotox on HEK293, HEK293 pGL4 and HEK293 NR2F6 (full length) compound was tested from 50 uM with dilution step 3.16 in duplicates. Human PBMC were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls without (100%) compounds.
  • FIGS. 26A and 26B show results of cytokine release by hPBMC and cytotox for
  • FIGS. 27A-27D show NR2F6 and LBD transient transfection, respectively, for
  • FIGS. 27E and 27F show toxicity of Compound D28.
  • FIGS. 28A-28D show the results of a cytokine release experiment for dog and human
  • FIGS. 29, 30 31A, 31B and 32 show exemplary methods of formulating the compounds that have been discussed herein.
  • FIGS. 33A and 33B and 34A-34D show NR2F6 and LBD transient transfection, respectively, for Compound E21.
  • FIGS. 35A to 35D show the results of a cytokine release experiment for dog and human PBMC, for Compound E21.
  • FIG. 36 shows additional compounds related to compound E21 that were tested herein.
  • FIG. 37 shows additional compounds that were synthesized and tested according to the present embodiments.
  • FIG. 38A and 38B, 39A-39D and 40A-40D show results of testing on Compound Fl.
  • FIG. 41 shows the general SAR strategy for testing Compound Fl and compounds related to it in structure; by dividing the active molecule into four domains (Domains A through D), and evaluating each domain independently to establish SAR trends.
  • FIG. 42 shows an exemplary synthesis of a boronate compound, and the results of other exemplary syntheses of compounds comprising boronate, and the relative proportions of resultant compounds.
  • FIG. 43 shows methods of synthesis of certain compounds found to be useful for the embodiments herein.
  • FIGS. 44A and 44B and 45A-D show NR2F6 and LBD transient transfection, respectively, for Compound Pl.
  • FIGS. 46A and 46B show the results of a cytokine release experiment for dog and human PBMC, for Compound P 1.
  • FIGS. 47A and 47B show NR2F6 agonist activity of various compounds discussed herein.
  • FIGS. 48-51 show synthesis of various additional compounds discussed herein.
  • FIGS. 52A and 52B show synthesis of Compounds Zl 19, Z120, Z121 and Z123.
  • FIG. 53-55 shows synthesis of additional compounds herein.
  • FIGS. 56A and 56B show Nr2F6 agonist activity for various compounds discussed herein.
  • FIGS. 57 and 58 show synthesis of various compounds discussed herein.
  • FIGS. 59A-D show further results for firefly, renila and pGL4 for Compounds D104,
  • FIGS. 60A-60C show further results for cytokines release inhibition for Compounds
  • FIGS. 61A-61E show further results of cytokine release by hPBMC for Compound
  • FIGS. 62A and 62B show stability in plasma (human plasma and rat plasma) and various pH solubility data for Compound D136.
  • FIGS. 63A and 63B show stability in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF), respectively, for Compound D136.
  • FIGS. 64A and 64B show microsomal stability in human liver microsomes and rat liver microsomes, respectively, for Compound D136.
  • FIGS. 65A and 65B show data for PK in rat plasma for Compound D136.
  • FIGS. 66A and 66B show data for PK in mice plasma for Compound D136.
  • FIGS. 67-70 show synthesis of additional compounds herein.
  • “disease” or“disorder” are used interchangeably and mean a disorder of structure or function in any living thing (including but not limited to a human, animal, or plant), especially one that produces specific signs or symptoms or that affects a specific location and is not simply a direct result of physical injury.
  • “mammal” means a warm-blooded vertebrate animal of a class that is distinguished by the possession of hair or fur, the secretion of milk by females for the nourishment of the young, and (typically) the birth of live young.
  • “human” means a person.
  • “animal” or“non-human mammal” means any non-human animal, including but not limited to: a canine (e.g., a dog), a feline (e.g, a cat), a rodent, an ungulate (e.g., a cow or ox), an equine (e.g., a horse), or a primate.
  • modulator means a molecule that alters the basal activity of
  • NR2F6 either positively (activates it or increases it) or negatively (represses, suppresses or decreases it).“Modulating” means the act of the modulator, either positive or negative.
  • a compound of the technology herein can be, in various embodiments, a modulator of NR2F6, for example, at an effective concentration or in an effective amount, but not be a modulator of any other receptor, or not a modulator at any other amount of NR2F6 or any other receptor. This can provide selectivity of effect of a compound of the technology herein when administered to a patient for treatment of any disease.
  • one diastereomer or one enantiomer of a compound of the present technology can display superior biological activity compared with the other.
  • separation of the diastereomeric mixture or the racemic material can be achieved by HPLC, optionally using a chiral column or by using a resolving agent such as camphonic chloride for the resolution of enantiomers.
  • a chiral compound described herein can also be directly synthesized using a chiral catalyst or a chiral ligand.
  • one deuterated or tritiated compound of the present technology can display superior biological activity compared with one or more others.
  • separation of the material can be achieved by one of ordinary skill in the art.
  • the present technology is directed to methods of modulating the immune system using compounds that alter activity of NR2F6.
  • compounds herein can be utilized for stimulation of NR2F6 activity, alone, or in combination with, for example, PKC activation. In certain embodiments, the compounds herein can be utilized for inhibition of NR2F6 activity, alone or in combination with, for example, anti-PDl, anti-PDLl or anti-CTLA4 antibodies.
  • the methods are directed to the stimulation of NR2F6 for, e.g., induction of immune inhibition, or stimulation of cellular proliferation without significant induction of differentiation. Inhibition of NR2F6 can be desirable in situations where a clinician seeks to augment immune response, or induce cellular differentiation.
  • inhibition of NR2F6 expression can be desirable in situations where inhibition of cancer or cancer stem cells is desired.
  • activation of NR2F6 expression can be desirable in situations where inhibition of the immune system is desired, for example, in connection with autoimmune disorders.
  • NRs by different structural classes of endogenous ligands, such as the steroid and thyroid hormones, lipids, vitamins and other biochemicals, is an important part of their function.
  • endogenous ligands such as the steroid and thyroid hormones, lipids, vitamins and other biochemicals.
  • the 48 NR family members are classified into subgroups based on the identification of endogenous ligands for each receptor.
  • the endocrine receptors include the steroid hormone receptors that bind steroid hormones and the heterodimeric receptors that partner with the retinoid X receptor and bind thyroid hormones, retinoids, and vitamin D.
  • SRMs selective receptor modulators
  • ER selective estrogen receptor
  • Adopted orphan receptors are a subtype of NRs that are subdivided into groups based on their ligands.
  • the lipid sensor receptor subtypes and their ligands include retinoid X receptor (9- cis -retinoic acid), peroxisome proliferator-activated receptors (PPARs) (fatty acids), liver X receptor (oxysterols), famesoid X receptor (bile acids), and pregnane X receptor, which binds cholesterol derivatives.
  • retinoid X receptor (9- cis -retinoic acid), peroxisome proliferator-activated receptors (PPARs) (fatty acids), liver X receptor (oxysterols), famesoid X receptor (bile acids), and pregnane X receptor, which binds cholesterol derivatives.
  • PPARs peroxisome proliferator-activated receptors
  • fatty acids fatty acids
  • liver X receptor oxysterols
  • any of these can be utilized by one of skill in the art to practice the methods of the present technology, which provides compounds useful for modulating the NR2F6 nuclear receptor.
  • Methods of modulating PPARs are also amenable to utilization in the context of the current technology, whose methodologies can, in various embodiments, be adapted for use with the compounds discussed herein for treatment of cancer or immune modulation.
  • PPARs three subtypes of the PPAR family are PPARa, PPARy, and
  • PPARr PPARr
  • PPARy is abundantly expressed in many cell types, where it regulates lipid metabolism, glucose homeostasis, tumor progression, and inflammation.
  • Polyunsaturated fatty acids, eicosanoids, prostaglandins, and linoleic acid have been identified as endogenous ligands for PPARy.
  • the thiazolidinedione class of compounds function as high-affinity synthetic agonists for PPARy subsequent to exposure to specific ligands.
  • PPARy forms a heterodimer complex with retinoid X receptor, which then mediates the target gene expression.
  • NR2F6 specific compounds can be substituted for those described for PPAR.
  • the enigmatic orphan receptor subtype can include the constitutive androstane receptor (androstane and many drugs or xenobiotics), hepatocyte nuclear factor-4, and steroidogenic factor- l/liver receptor homolog l(LRH-l) (phospholipids), retinoid acid-related orphan receptor (cholesterol and retinoic acids), and estrogen-related receptor (estrogens). These can be useful in methods of performing immunotherapy that include NR2F6 modulators.
  • the orphan receptors are the third class of NRs.
  • the crystal structure of the ligand binding domain of the orphan receptor Nurrl shows that several hydrophobic residues protrude into the ligand-binding pocket, and atypical coactivator-binding site is lacking, suggesting that some orphan receptors may not bind ligands.
  • the orphan receptors play important roles in cellular homeostasis and diseases including cancer, and several recent reports document the expression and potential functions of orphan receptors in different tumors and cancer cell lines.
  • Breast tumors are routinely classified as ER + or ER . and expression of ER has prognostic significance that influences selection of therapeutic regimens.
  • analysis of ER + and ER tumors for expression (mRNA) of all 48 NRs also demonstrated the important prognostic significance of several orphan receptors.
  • NR4A Neuronal Component NR4A
  • NR2F6 v-erbA -related protein (EAR2)] receptors
  • ER + and ER combined tumors NR4A
  • NR2F6 v-erbA -related protein (EAR2)] receptors
  • EAR2F6 v-erbA -related protein (EAR2)] receptors
  • EAR2F6 v-erbA -related protein
  • NR profiling of the NCI60 cancer cell panel demonstrated that relative expression levels of some orphan receptors also correlated with drug sensitivity.
  • cancer cell sensitivity to microtubule-disrupting drugs has been found to be enhanced in cells expressing low levels ofNR2F6 and COUP-TFII, whereas high levels of the orphan receptor tailless (TEX, NR2E1) correlated with sensitivity to 9-fluoroprednisolone.
  • NR2F6 means“nuclear receptor subfamily 2, group F, member 6” or“Ear2.”
  • Nuclear receptors are transcription factors that regulate the expression of specific target genes, thereby orchestrating a wide array of cellular processes including cellular activation, development and disease progression.
  • the nuclear receptor super-family includes receptors that bind to hormones and orphan receptors with yet undefined endogenous ligands.
  • NR2F6 can be a target in cancer immunotherapy or autoimmune suppression.
  • the COUP-TF orphan receptors are preferentially expressed in the central nervous system and organs that depend on the interaction between mesenchyme and epithelial layers.
  • the three mammalian COUP-TF family members are NR2Fl/Ear3, NR2F2/Arpl and NR2F6.
  • the established target genes of said COUP-TF family members are apolipoproteins and retinoic acid-, peroxisome-, oxytocin-, estrogen- and vitamin D receptors.
  • yeast 1 -hybrid screen and in vitro assays with recombinant NR2F6 it was found that the TGACCT direct-repeat motif is the DNA binding sequence of NR2F6, and that overexpression of NR2F6 induces repression of the renin gene transcription in a DNA-binding-specific manner.
  • Wild type human/animal NR2F6 is known to possess the following nucleotide sequence: 1 gtgcagcccg tgcccccgc gcgccggggc cgaatgcgcg ccgcgtaggg tcccccgggc 61 cgagaggggt gcccggaggg aagagcgcgg tgggggcgccccccgc tgccctgggg 121 ctatggccat ggtgaccggc ggctggggcg gcccggcgg cgacacgaac ggcgtggaca 181 aggcgggcgg ctacccgcgc gcggccgagg acgactcggc ctcgccccc ggtgccgcca 241 gcgacgccg
  • the present technology is directed to compounds that bind to a portion or all of an NR2F6 molecule; or any molecule that is, in various embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identical to the amino acid sequence of NR2F6.
  • the terms“agonist” or“activator” are used interchangeably and mean a compound or substance capable of fully or partially stimulating the physiologic activity of one or more specific receptors.
  • an agonist can therefore stimulate the physiological activity of a receptor such as NR2F6 upon binding of said compound substance to said receptor.
  • an“agonist” or“activator” can be used to“activate,” “stimulate” or“increase activity” of a cell.
  • binding of an“agonist” or“activator” to a given receptor can mimic the action of an endogenous ligand binding to said receptor.
  • a given receptor e.g., NR2F6
  • the term“agonist” also encompasses partial agonists or co-agonists or co-activators.
  • an“agonist” or“activator” of NR2F6 as used herein can also be capable of stimulating the function of a given receptor, such as NR2F6, by inducing or enhancing the expression of the nucleic acid molecule encoding for said receptor.
  • an agonist or activator of NR2F6 can, in certain embodiments, lead to an increased expression level of NR2F6 (e.g., increased level of NR2F6 mRNA, NR2F6 protein) which is reflected in an increased activity of NR2F6.
  • This increased activity can be measured or detected by the methods herein.
  • an activator of NR2F6 in accordance with the present technology can, in certain embodiments, also encompass transcriptional activators of NR2F6 expression that are capable of enhancing NR2F6 function.
  • “agonist” includes a partial agonist.
  • “Partial agonists” mean candidate molecules that behave like agonists, but that, even at high concentrations, cannot activate NR2F6 to the same extent as a full agonist.
  • the increased expression or activity of NR2F6 by an agonist or activator of NR2F6 can lead to decreased activity (or expression) of components of the NR2F6-dependent signaling pathway; in particular the activity of NF-AT and AP-l can be decreased.
  • NF-AT/AP-l regulate transcription/expression of further "downstream" components of the NR2F6-dependent signaling pathway, such as IL-2, IL-17 and/or IFN-gamma.
  • a decrease in NF-AT/AP-l activity can result in a decreased transcription of these "downstream” components (e.g., IL-2, IL-17 and/or IFN-gamma) which in turn leads to a suppression of an immune response.
  • an agonist or activator of NR2F6 can lead to suppression of an immune response.
  • the use of potent agonists/activators of NR2F6 can lead to a higher expression or activity of NR2F6.
  • NR2F6 can be considered its own“agonist” or“activator.”
  • NR2F6 can lead to enhanced NR2F6 activity, thus agonizing NR2F6 function.
  • NR2F6 as defined herein can, in certain embodiments, be used for the treatment of a disease related to an augmented immune response.
  • NR2F6 can be used in accordance with certain embodiments of the present technology, wherein NR2F6 is any of the following: (a) a polypeptide comprising an amino acid encoded by a nucleic acid molecule having the nucleic acid sequence of NR2F6; (b) a polypeptide having an amino acid sequence of NR2F6; (c) a polypeptide encoded by a nucleic acid molecule encoding a peptide having an NR2F6 amino acid sequence; (d) a polypeptide comprising an amino acid encoded by a nucleic acid molecule hybridizing to the complementary strand of nucleic acid molecules as defined in (a) or (c) and encoding a NR2F6 or a functional fragment thereof; (e) a polypeptide having at least 60% homology to the polypeptide of any one of (a) to (d), whereby said polypeptide is a NR2F6 or a functional fragment thereof; or (f
  • NR2F6 is also shown in the appended examples. As demonstrated therein, overexpression (about 5- fold increase over normal expression level) can lead to a diminished IL-2 activity/expression and consequently to a reduced IL-2 amount, resulting in a reduced immune response.
  • agonists/activators of NR2F6 are useful in the treatment of diseases where suppression of the immune response is desired (e.g., diseases with an overstimulated immune response, such as allergies and multiple sclerosis).
  • diseases with an overstimulated immune response such as allergies and multiple sclerosis.
  • the term“overexpression” means that the NR2F6 activity/expression is, in various embodiments, at least l-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, or at least 25 -fold increased in comparison to a (control) standard value as defined herein, wherein a value of 25 fold expression level or greater over normal can be considered as a maximum overexpression level.
  • “antagonist” or“inhibitor” are used interchangeably and mean a compound or substance capable of fully or partially suppressing or inhibiting the physiologic activity of one or more specific receptors.
  • an antagonist can therefore suppress the physiological activity of a receptor upon binding of said compound substance to said receptor but does not activate the receptor and therefore blocks the activity of other agonists.
  • an“antagonist” or“inhibitor” can be used to“deactivate,”“inhibit,” “suppress” or“decrease activity” of a cell.
  • the terms“immune response” or“immune reaction” are used interchangeably and mean the response or reaction of the immune system to an antigen.
  • immune cells are activated in such way that one or more specific functions of said immune cells can be induced.
  • The“immune cells” can include, but are not limited to, B cells, T cells, neutrophils, eosinophils, basophils, mast cells, macrophages and dendritic cells.
  • said“specific fimction(s) of activated immune cells” can include, but are not limited to, secretion of antibodies, presentation of antigen, proliferation of said immune cells, secretion of cytokines such as interleukin-2 (IL-2), interleukin- 17 (IL-17), interleukin- 18 (IL-18), or interferon gamma (IFNgamma), expression of regulatory-, activation- or adhesion molecules, and the ability to induce apoptosis or cytolysis.
  • cytokines such as interleukin-2 (IL-2), interleukin- 17 (IL-17), interleukin- 18 (IL-18), or interferon gamma (IFNgamma)
  • IFNgamma interferon gamma
  • the term“antigen” means any substance capable of inducing an immune response.
  • An antigen typically is associated with a foreign substance (i.e. a“non-self antigen”).
  • a“self antigen” an own body-derived substance (i.e., a“self antigen”) can also induce an immune response.
  • the term“immune response” also encompasses autoimmune responses or autoimmune reactions.
  • the technology herein is directed to a method of treating or reducing the effect of an autoimmune response, reaction, disease or disorder, the method comprising activating the NR2F6 target in isolated immune cells by binding them with a compound according to the present technology.
  • “treating a cancer,”“inhibiting cancer” or“reducing cancer growth” are used interchangeably and mean inhibiting or preventing oncogenic activity of cancer cells.
  • Oncogenic activity can comprise stimulating migration, invasion, drug resistance, cell survival, anchorage-independent growth, non-responsiveness to cell death signals, angiogenesis, or combinations thereof of the cancer cells.
  • agents suitable for use in treating a cancer or reducing the growth rate of a tumor include, but are not limited to, small organic molecules, peptides, proteins, peptidomimetics, nucleic acids, antibodies and combinations thereof.
  • such agents can be formulated with a pharmaceutically acceptable carrier, and can be administered: intravenously, orally, buccally, sublingually, parenterally, by inhalation, by nasal administration, by insufflation, by topical application, transdermally, by cutaneous injection, or by local administration.
  • An agent can additionally be administered in conjunction with one or more anti cancer chemotherapeutic agent in an additive or synergistic manner.
  • cancer As used herein,“cancer,”“cancer cell,”“tumor” and“tumor cell” are used interchangeably and mean a group of diseases characterized by uncontrolled, abnormal growth of cells (e.g., a neoplasia). These can include solid tumor cancer, liquid tumor cancer and metastatic disease. In some forms of cancer, the cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body (“metastatic cancer”).
  • ex vivo activated lymphocytes “ex vivo activated lymphocytes,”“lymphocytes with enhanced antitumor activity” and“dendritic cell cytokine induced killers” are used interchangeably and mean composition of cells that have been activated ex vivo and subsequently reintroduced within the context of the current disclosure.
  • lymphocyte this also includes heterogeneous cells that have been expanded during the ex vivo culturing process including dendritic cells, NKT cells, gamma delta T cells, and various other innate and adaptive immune cells.
  • cancer means any disease caused by uncontrolled division or growth of abnormal cells, and any malignant growth or tumor resultant from such uncontrolled division or growth.
  • cancer includes all types of cancer or neoplasm or malignant tumors found in animals, including leukemias, carcinomas and sarcomas.
  • cancers include, but are not limited to: cancer of the brain, skin (including melanoma), breast, cervix, head and neck, kidney, lung, non-small cell lung, mesothelioma, sarcoma, any internal organ (including bladder, stomach, liver, pancreas, uterus, ovary, prostate, colon) and Medulloblastoma.
  • leukemia means a broadly progressive, malignant disease of the hematopoietic organs or systems and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow.
  • Leukemia diseases include, but are not limited to: acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, B cell lymphoma, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic
  • carcinoma means a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues, or resist physiological and non- physiological cell death signals and give rise to metastases.
  • exemplary carcinomas include, but are not limited to: acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiennoid carcinoma, carcinoma epithelia
  • intraepidermal carcinoma intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, and carcinoma scroti.
  • sarcoma means a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar, heterogeneous, or homogeneous substance. Sarcomas include, but are not limited to:
  • chondrosarcoma fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms’ tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B
  • Additional exemplary neoplasias include, for example, Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, lung cancer, rhabdomyosarcoma, primary
  • thrombocytosis primary macroglobulinemia, small-cell lung tumors, primary brain tumors, stomach cancer, colon cancer, malignant pancreatic insulanoma, malignant carcinoid, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, and adrenal cortical cancer.
  • the cancer treated is a melanoma.
  • the term“melanoma” means a tumor arising from the melanocytic system of the skin or other organs.
  • Melanomas include, for example, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma subungual melanoma, and superficial spreading melanoma.
  • the term“polypeptide” is used interchangeably with“peptide,”“altered peptide ligand” and“fluorocarbonated peptides.”
  • the term“pharmaceutically acceptable carrier” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the therapeutic compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions herein.
  • a T cell includes any of: a CD8-positive T cell (cytotoxic T cell: CTL), a CD4 + T cell (helper T cell), a suppressor T cell, a regulatory T cell such as a controlling T cell, an effector cell, a naive T cell, a memory T cell, an alpha (a) beta (b) T cell expressing TCR a and b chains, and a gamma (g) delta (d) T cell expressing TCR g and d chains.
  • the T cell includes a precursor cell of a T cell in which differentiation into a T cell is directed.
  • “cell populations containing T cells” include, in addition to body fluids such as blood (peripheral blood, umbilical blood etc.) and bone marrow fluids, cell populations containing peripheral blood mononuclear cells (PBMC), hematopoietic cells, hematopoietic stem cells, umbilical blood mononuclear cells etc., which have been collected, isolated, purified or induced from the body fluids.
  • body fluids such as blood (peripheral blood, umbilical blood etc.) and bone marrow fluids
  • PBMC peripheral blood mononuclear cells
  • hematopoietic cells hematopoietic stem cells
  • umbilical blood mononuclear cells etc. which have been collected, isolated, purified or induced from the body fluids.
  • hematopoietic cells can be used in connection with the embodiments of the present technology. These cells may have been activated by cytokine such as IL-2 in vivo or ex vivo, and can be collected in any known way, for example, collected from a living body; obtained via ex vivo culture, for example, a T cell population obtained by a method herein; or obtained by freeze preservation.
  • cytokine such as IL-2 in vivo or ex vivo
  • the term“antibody” means both intact molecules as well as fragments thereof that include the antigen -binding site.
  • Whole antibody structure is often given as H 2 L 2 and refers to the fact that antibodies commonly comprise 2 light (L) amino acid chains and 2 heavy (H) amino acid chains. Both chains have regions capable of interacting with a structurally complementary antigenic target. The regions interacting with the target are referred to as “variable” or “V” regions and are characterized by differences in amino acid sequence from antibodies of different antigenic specificity.
  • the variable regions of either H or L chains contain the amino acid sequences capable of specifically binding to antigenic targets. Within these sequences are smaller sequences dubbed "hypervariable" because of their extreme variability between antibodies of differing specificity.
  • CDR regions Such hypervariable regions are also referred to as “complementarity determining regions” or “CDR” regions. These CDR regions account for the basic specificity of the antibody for a particular antigenic determinant structure.
  • the CDRs represent non-contiguous stretches of amino acids within the variable regions but, regardless of species, the positional locations of these critical amino acid sequences within the variable heavy and light chain regions have been found to have similar locations within the amino acid sequences of the variable chains.
  • the variable heavy and light chains of all antibodies each have 3 CDR regions, each non-contiguous with the others (termed Ll, L2, L3, Hl,
  • H2, H3 for the respective light (L) and heavy (H) chains.
  • the antibodies discussed herein can also be wholly synthetic, wherein the polypeptide chains of the antibodies are synthesized and, possibly, optimized for binding to the polypeptides disclosed herein as being receptors.
  • Such antibodies can be, in various embodiments, chimeric or humanized antibodies, and can be fully tetrameric in structure, or can be dimeric and comprise only a single heavy and a single light chain.
  • the terms“effective amount” or“therapeutically effective amount” are used interchangeably and mean a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of a disease state being treated or to otherwise provide a desired pharmacologic or physiologic effect, especially enhancing T cell response to a selected antigen.
  • the precise dosage in any given embodiment can vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease, and the treatment being administered.
  • the terms“individual,”“host,”“subject” and“patient” are used interchangeably and mean a mammal, including, but not limited to, primates, for example, human beings, as well as rodents, such as mice and rats, and other laboratory animals or any other animals mentioned herein.
  • the compounds or compositions discussed herein can be general compounds or compositions useful for any purpose, pharmaceutical compounds or compositions, or animal (e.g., veterinary) compounds or compositions.
  • “treat,”“treating” or“treatment” means an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder; and includes: (i) preventing a pathologic condition from occurring (e.g., prophylaxis); (ii) inhibiting the pathologic condition or arresting its development (e.g., slowing or stopping proliferation of cancer cells or tumor growth); (iii) relieving the pathologic condition; or (iv) diminishing symptoms associated with the pathologic condition.
  • a pathologic condition from occurring (e.g., prophylaxis)
  • inhibiting the pathologic condition or arresting its development e.g., slowing or stopping proliferation of cancer cells or tumor growth
  • relieving the pathologic condition e.g., slowing or stopping proliferation of cancer cells or tumor growth
  • diminishing symptoms associated with the pathologic condition e.g., slowing or stopping proliferation of cancer cells or tumor growth
  • the term“treatment regimen” means a treatment of a disease or a method for achieving a desired physiological change, such as increased or decreased response of the immune system to an antigen or immunogen, such as an increase or decrease in the number or activity of one or more cells, or cell types, that are involved in such response.
  • the treatment or method comprises administering to an animal, such as a mammal, a sufficient amount of one or more (in certain embodiments two or more) chemical agents or components of said regimen to effectively treat a disease or to produce said physiological change.
  • the two or more agents or components are administered together, such as part of the same composition, or administered separately and independently at the same time or at different times (i.e.. administration of each agent or component is separated by a finite period of time from one or more of the agents or components).
  • administration of said one or more agents or components achieves a result greater than that of any of said agents or components when administered alone or in isolation.
  • the terms“anergy” or“unresponsiveness” are used interchangeably and include unresponsiveness to an immune cell to stimulation, for example, stimulation by an activation receptor or cytokine.
  • Anergy can occur due to, for example, exposure to an immune suppressor or exposure to an antigen in a high dose. Such anergy is generally antigen-specific, and can continue even after completion of exposure to a tolerized antigen.
  • the anergy in a T cell and/or NK cell can be characterized by failure of production of cytokine, e.g., interleukin (IL)-2.
  • IL interleukin
  • the T cell anergy and/or NK cell anergy can occur in part when a first signal (signal via TCR or CD- 3) is received in the absence of a second signal (costimulatory signal) upon exposure of a T cell and/or NK cell to an antigen.
  • the terms“enhanced function of a T cell,”“enhanced cytotoxicity” and“augmented activity” are used interchangeably and mean that the effector function of the T cell or NK cell is improved.
  • the enhanced function of the T cell or NK cell can include any of the following: an improvement in the proliferation rate of the T cell or NK cell, an increase in the production amount of cytokine, or an improvement in cytotoxity.
  • the enhanced function of the T cell or NK cell includes cancellation or suppression of tolerance of the T cell or NK cell in the suppressed state such as the anergy (unresponsive) state, or the rest state, that is, transfer of the T cell or NK cell from the suppressed state into the state where the T cell or NK cell responds to stimulation from the outside.
  • the suppressed state such as the anergy (unresponsive) state, or the rest state, that is, transfer of the T cell or NK cell from the suppressed state into the state where the T cell or NK cell responds to stimulation from the outside.
  • “expression” means generation of mRNA by transcription from nucleic acids such as genes, polynucleotides, and oligonucleotides, or generation of a protein or a polypeptide by transcription from mRNA. Expression can be detected by any method including RT- PCR, Northern Blot, or in situ hybridization.
  • “suppression of expression” means a decrease of a transcription product or a translation product in a significant amount as compared with the case of no suppression. The suppression of expression herein shows, in various embodiments, a decrease of a transcription product or a translation product in amounts of 30% or more, 50% or more, 70% or more, or 90% or more.
  • augmented immune response means characterized by a particularly strong response or reaction of the immune system to the presence of an antigen. Under normal, non- pathological conditions, immune responses are regulated in a tightly controlled fashion. Moreover, immune responses are self-limiting and decline in time after exposure to the antigen. In case of an “augmented immune response” however, the immune response can be hypersensitive, i.e., the immune response can cause damage to the organism's own cells or tissue in presence of an antigen. Furthermore, in some cases of an“augmented immune response,” for example in auto-immune diseases or disorders or in transplant rejects (and the like), the immune system can fail to distinguish between self and non-self substances. As used herein,“disease related to an augmented immune response” accordingly relates to any disease or disorder in which an augmented immune response is etiological for, associated with, secondary to or the resultant of said disorder.
  • an augmented immune response can be determined by directly or indirectly measuring parameters that are indicative for the magnitude of the immune response or reaction to an antigen, and comparing the outcome of said measurement with the outcome of the same test in a physiologically normal subject.
  • Parameters indicative for the magnitude of the immune response/reaction can include, but are not limited to: the presence or quantity of (specific) antibodies; the presence or quantity of (specific) immune cells; the presence or quantity of (specific) cytokines; or the presence or quantity of (specific) regulatory-, activation- or adhesion molecules.
  • the disease related to an augmented immune response is any of the following: [00143] an acute or chronic transplant rejection, including septic shock, infections caused by bacteria including MRSA and viruses;
  • a dermatological disease for example, psoriasis, atopic dermatitis or contact allergy;
  • T- and B-cell-mediated inflammatory disease for example, asthma or chronic obstructive pulmonary disease (COPD);
  • COPD chronic obstructive pulmonary disease
  • graft-versus-host disease for example, acute (or fulminant) graft-versus-host disease or chronic graft-versus-host disease; or
  • auto-immune disease for example, multiple sclerosis, inflammatory bowel disease, like ulcerative colitis or Behcet's disease; vasculitis, lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, polymyositis, mixed collective tissue disease (MCTD) rheumatoid arthritis, diabetes mellitus (whether Type 1 or Type 2), celiac disease, celiac sprue disease, atherosclerosis, Goodpasture's syndrome, Grave's disease, autoimmune
  • hepatitis/hepatic autoimmune diseases autoimmune thrombocytopenic purpura, granulomatosis (e.g., morbus Wegener), Sjogren’s Syndrome, scleroderma, alopecia areata or autoimmune hemolytic anemia.
  • T cell receptor (TCR) stimulation activates NF-AT/AP-l, a family of transcription factors that is of particular importance during immune cell activation.
  • NF-AT mediates the transcriptional induction of “cell fate -determining genes,” which govern as diverse outcomes as activation, anergy or apoptosis.
  • the rise of intracellular Ca 2+ triggered by antigen binding to the TCR can lead to the activation of calcineurin's phosphatase activity.
  • NF-AT nuclear import of NF-AT.
  • feedback inhibition mediated via GSK3 (glycogen synthase kinase 3), CK1 (casein kinase 1) and DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) protein kinases can counter-regulate NF-AT nuclear occupancy by rephosphorylation, which induces the nuclear export of NF-AT and the abort of immune activation-associated gene transcription.
  • NF- AT family members are also subject to regulation in the nucleus through their ability to directly interact with other transcriptional regulatory factors.
  • NF-AT requires a protein partner for high- affinity binding at most DNA sites.
  • NF-AT complexes mostly contain cell type- or cell lineage- specific protein binding partners.
  • NF-AT forms complexes with GATA proteins.
  • the present technology is directed to agonists or activators of NR2F6 for the treatment of a disease related to an augmented immune response.
  • the present technology is directed to the use of an agonist or activator of NR2F6 for the preparation of a medicament for the treatment of a disease related to an augmented immune response.
  • the utilization of NR2F6 modulating compounds for alteration of immune response can be utilized by administering in patients suffering from cancer in which increased efficacy of a cancer vaccine is desired. In these situations, inhibition of NR2F6 is desirable, optionally in addition to immune stimulation.
  • the compositions herein can comprise any of the following:
  • agonists/activators of NR2F6 in combination with: (i) one or more additional immune enhancers (ii) CAR-T cell therapy (which can reduce side effects); or (iii) autologous cell therapies, e.g., dendritic cells, anti -PD 1 and antiCTLA4 antibodies, PMBC, or umbilical vein cord blood-derived cells.
  • additional immune enhancers e.g., CAR-T cell therapy (which can reduce side effects); or
  • autologous cell therapies e.g., dendritic cells, anti -PD 1 and antiCTLA4 antibodies, PMBC, or umbilical vein cord blood-derived cells.
  • additional immune suppressants e.g., one or more additional immune suppressants
  • CAR-T cell therapy which can reduce side effects
  • autologous cell therapies e.g., dendritic cells, anti -PD 1 and antiCTLA4 antibodies, PMBC, or umbilical vein cord blood-derived cells.
  • inhibitor compounds of NR2F6 are administered with a cancer antigen, said cancer antigens include ROBO-4.
  • the antigens can be used to replace ROBO-4.
  • These can include any of the following: a) Fos-related antigen 1; b) LCK; c) FAP; d) VEGFR2; e) NA17; f) PDGFR-beta; g) PAP; h) MAD-CT-2; i) Tie-2; j) PSA; k) protamine 2; l)legumain; m) endosialin; n) prostate stem cell antigen; o)carbonic anhydrase IX; p) STn; q) Page4; r) proteinase 3; s) GM3 ganglioside; t) tyrosinase; u) MART1; v) gplOO; w) SART3
  • the assessment of compounds for NR2F6 modulating activity is performed utilizing means known in the art, such as described in U.S, Patent No. 9,091,696.
  • Compounds useful for the screening and modification for enhanced NR2F6 modulatory activity include: CAR Agonists such as 5 -Dihydroprogesterone, 6,7-Dimethylesculetin, Amiodarone, Artemisinin, Benfuracarb, Carbamazepine, Carvedilol, Chlorpromazine, Chrysin, CITCO,
  • CAR Agonists such as 5 -Dihydroprogesterone, 6,7-Dimethylesculetin, Amiodarone, Artemisinin, Benfuracarb, Carbamazepine, Carvedilol, Chlorpromazine, Chrysin, CITCO,
  • Clotrimazole Cyclophosphamide, Cypermethrin, DHEA, Efavirenz, Ellagic acid, Griseofulvin, Methoxychlor, Mifepristone, Nefazodone, Nevirapine, Nicardipine, Octicizer, Permethrin,
  • CAR Antagonists such as 3.17p-Estradiol. 3a-Androstanol, 3a-Androstenol, 3 -Androstanol, l7-Androstanol, AITC, Ethinyl estradiol, Meclizine, Nigramide J, Okadaic acid, PK-11195, S-07662, T-0901317.
  • FXR Agonists such as Bile acids, cafestol, Chenodeoxycholic acid, Fexaramine, GW- 4064, Obeticholic acid.
  • FXR Antagonists such as Guggulsterone.
  • LXR Agonists such as 22R- Hydroxycholesterol, 24S-Hydroxycholesterol, 27-Hydroxycholesterol, Cholestenoic acid, DMHCA, GW-3965, Hypocholamide, T-0901317.
  • PPAR-alpha Agonists such as 15-HETE, 15-HrETE,
  • Aleglitazar Aluminum clofibrate, Arachidonic acid, Bezafibrate, Clofibrate, CP -775146, DHEA, Elafibranor, Fenofibrate, Gemfibrozil, GW-7647, Leukotriene B4, LG-101506, LG-100754,
  • Perfluorononanoic acid Perfluorooctanoic acid, Pioglitazone, Saroglitazar, Sodelglitazar,
  • Tesaglitazar Tetradecylthioacetic acid, Troglitazone, WY- 14643.
  • PPAR-alpha Antagonists such as GW-6471, MK-886.
  • PPAR-delta Agonists such as 15-HETE, 15-HrETE, Arachidonic acid,
  • PPAR-delta Antagonists such as FH-535, GSK-0660, GSK-3787.
  • PPAR gamma agonists such as 5-Oxo-ETE, 5-Oxo-l5-hydroxy-ETE, 15 -Deoxy-A 12,14-prostaglandin J2, 15-HETE, 15-HrETE, Aleglitazar, Arachidonic acid, Berberine, Bezafibrate, Ciglitazone,
  • SSPARMS such as BADGE, EPI-001, INT-131, MK-0533, S26948.
  • PPAR gamma antagonists such as FH-535, GW-9662, SR-202, T-0070907.
  • PPAR nonselective agonists such as Ciprofibrate, Clinofibrate, Clofibride, Englitazone, Etofibrate, Farglitazar, Netoglitazone, Ronifibrate,
  • PXR Agonists such as 5a-Dihydroprogesterone, 5 -Dihydroprogesterone, l7a-Hydroxypregnenolone ,l7a-Hydroxyprogesterone, A4-Androstenedione, A5-Androstenediol, D5- Androstenedione, AA-861, Allopregnanolone, Alpha-Lipoic acid, Ambrisentan, AMI-193,
  • PXR Antagonist such as Ketoconazole.
  • RAR Agonists such as 9CDHRA, 9-cis-Retinoic acid (alitretinoin), AC-261066, AC-55649, Acitretin, Adapalene, all-trans-Retinoic acid (tretinoin), AM-580, BMS-493, BMS-753, BMS-961, CD-1530, CD-2314, CD-437, Ch-55, EC 23, Etretinate, Fenretinide,
  • RAR Antagonists such as BMS-195614, BMS-493, CD-2665, ER-50891, LE-135, MM-11253.
  • RXR Agonists such as 9CDHRA, 9-cis-Retinoic acid (alitretinoin), all-trans-Retinoic acid (tretinoin), Bexarotene, CD 3254, Docosahexaenoic acid, Fluorobexarotene, Isotretinoin, LG- 100268, LG-101506, LG-100754, Retinoic acid, Retinol (vitamin A), SR-l 1237.
  • RXR Antagonists such as HX-531, HX-630, LG-100754, PA-452, UVI-3003.
  • TR Agonists such as Dextrothyroxine, GC-l, Levothyroxine, Liothyronine, Thyroxine, Tiratricol, Triiodothyronine.
  • AC 1 MLR07 4-(2-methylimidazo [ 1 ,2-a]pyridin-3 -yl)-N -(3 -methylphenyl)- 1 ,3 -thiazol-2-amine, AGN-PC-09PPXW, Compound l5Jf, AC1MEEXM, ST50941838, [2-[(3-carbamoylthiophen-2- yl)amino]-2-oxoethyl] 2-naphthalen-l-ylacetate, F0239-0029, AC1OBZ0O, ST4126227, l-[(4- bromophenyl)methyl]-2-methylbenzimidazole, SMR000718391, MLS002694437, Chlormidazole, 2- methyl-l-(2-methylbenzyl)-lH-benzimidazole, MLS003119103, Ambcb904563 l l, AGN-PC- 04RX4B, MLS001
  • Additional compounds include 6-formylindolo (3,2-B) carbazole, 4-hydroxyphenylretinamide, 3,5-Dilodo-L-tyrosine, Rifampicin, and Z30972355.
  • a pharmaceutical composition comprising a NR2F6 modulator, such as a NR2F6 inhibitor or NR2F6 activator, for use in the methods described herein.
  • a pharmaceutical composition comprising an effective amount of a NR2F6 inhibitor or NR2F6 activator in admixture with a pharmaceutically acceptable carrier, excipient or diluent.
  • Such pharmaceutical composition can be, in various embodiments, a composition suitable for administering to a human, or to an animal (i.e., a veterinary pharmaceutical composition).
  • compositions herein can be used to inhibit NR2F6; or to activate NR2F6.
  • the pharmaceutical composition is used to treat a disease or a hematopoietic condition as described herein.
  • the NR2F6 inhibitors or NR2F6 activators can be formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo.
  • biologically compatible form suitable for administration in vivo means a form of the substance to be administered in which any toxic effects are outweighed by the therapeutic effects.
  • the substances herein can be administered to living organisms including humans, and animals. Administration of a therapeutically active amount of the pharmaceutical compositions of the present disclosure is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result.
  • a therapeutically active amount of a substance can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of inhibitor to elicit a desired response in the individual. Dosage regime can be adjusted to provide the optimum therapeutic response. For example, several divided doses can be administered daily or the dose can be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • the active substance can be administered by, e.g., injection
  • the active substance can, in certain embodiments, be coated in a material to protect the compound from the action of enzymes, acids and other natural conditions which could inactivate the compound.
  • the active substance can be formulated into delayed release formulations such that NR2F6 can be inhibited or activated for longer periods of time than a conventional formulation.
  • a method herein includes the following steps: (a) extraction of an amount of a patient’s cellular material, including, but not limited to: blood, saliva, sweat, or any portion of a tumor known or believed to be in a diseased state; (b) isolating immune cells from the cellular material; (c) inhibiting or activating the NR2F6 target in the extracted immune cells; and (d) re-administering the immune cells (for example, by injection) to the patient’s body. This can have the effect of“reprogramming” the immune cells to attack tumors or other invasive cells.
  • other types of a patient’s cellular material can also be extracted. These include, for example, any part of the blood (blood serum, red blood cells, white blood cells, plasma, platelets), any other material from the body that includes the patient’s cells (for example, skin, hair, nails, saliva, cerebrospinal fluid, intracellular fluid, extracellular fluid, intravascular fluid, interstitial fluid, lymphatic fluid, transcellular fluid, exudates, lymph, sweat, sebum or serous fluid).
  • the re-administering of the immune cells to the patient’s body can be done by injection, introduction through the nose or mouth (for example, inhalation), skin or mucous membranes.
  • the present technology is directed to compounds alone or in combination with another medicament.
  • compounds herein include stereoisomers (including, e.g., enantiomers, diastereomers, cis-trans and E-Z isomers, conformers and atropisomers), tautomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts and mixtures thereof.
  • Compositions containing a compound herein can be prepared by conventional techniques, and can appear in conventional forms, for example, oral dosage forms; or any ingestible, inhalable (e.g., through the mouth, nose or mucosa); or topical applications, e.g. , applicable to the skin, nails, eyes or the like.
  • These can include, in various embodiments, capsules, tablets, pills, cachets, dispersible granules, lozenges, aerosols, solutions, powders, suspensions, emulsions, gels, mousses, foams, drops, lotions, creams, paste, dragees, suppositories and any application deliverable to the body of a user.
  • dosages and compounds herein can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms, including, but not limited to, by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously,
  • compositions described herein can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle.
  • the compositions can include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • a powder or tablet according to a dosage form herein can contain about 5 to about 75%, about 10 to about 70%, or about 15 to about 65% of the active compound.
  • Suitable carriers include, but are not limited to: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • carriers for certain dosages can include aqueous solutions of dextrose, saline, water, organic solvents including ethanol, glycerol, propylene glycol, oils including peanut oil or sesame oil; or polyoxyethylene-block polymers.
  • Aqueous solutions or suspensions can be made by dispersing the finely divided active component in water or another solvent with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents.
  • the compounds or dosages herein can also be incorporated into liposomes or micelles, or administered via transdermal pumps or patches.
  • Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition.
  • co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil; and in various embodiments, are present in amounts of about 0.01 to about 10%, about 0.05 to about 5% or about 0.1 to about 3% by weight.
  • viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing; and in various embodiments, are present in amounts of about 0.01 to about 10%, about 0.05 to about 5% or about 0.1 to about 3% by weight.
  • compositions herein can, in certain embodiments, additionally include components to provide sustained release or comfort.
  • components include, but are not limited to, high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, finely-divided drug carrier substrates, emollients, humectants, moisturizers, essential oils, oils, lipids, fatty acids, glycerides, extracts of natural ingredients, soaps and waxes.
  • the present disclosure includes various compounds that were found to be modulators of NR2F6 activity and NR2F6 utilizing compounds, and the immune modulation and modulation of cancer stem cell activity. Exemplary compounds and methods are shown in the attached FIGS. 1-58. These compounds were initially found to be modulators of NR2F6 activity and NR2F6 utilizing compounds, and the immune modulation and modulation of cancer stem cell activity.
  • a compound herein can be in amorphous form, crystalline form, or a mixture thereof; as well as any polymorph or amorphous form, a solvate, a hydrate or an unsolvated form.
  • hit criteria was ACT% > DMSO control + 5*SD (DSO control) at 10 mM, or any compound with S/B > 2.
  • hit criteria was ACT% > DMSO control + 3*SD (DSO control) in each replicate at 10 mM.
  • hit criteria was mean ACT ⁇ DMSO control + 3*SD (DMSO control) with ERa transient transfection in duplicate at 10 pM.
  • Table 1 shows screening results from a first set of compounds.
  • FIGS. 16A and 16B show results of cytokins release by hPBMC and cytotox for Compound Cl 1.
  • the Compound was tested at 1.25, 2.5, 5, 10, 25 and 50 uM in duplicates.
  • HEK293, HEK293 pGL4 and HEK293 NR2F6 (full length) cmpd was tested from 50 uM with dilution step 3.16 in duplicates.
  • the human PBMC were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) w/o compounds.
  • R, Rl and R2 are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • RA, RB, R1-R8, X, Q, Ql, Q2, or A can be any of the following: Me, OMe, Br, N, H, Cl, F or N0 2 .
  • any of R, RA, RB, R1-R8, X, Q, Ql, Q2, or A can be any of the following: 4-Me, 4-OMe, 4-Br, 4-t-Bu, 3,4-di-Me, 4-C1, 3,4-di-Cl, 3-C1-4-F, 2-F, 3-C1, 3-CH 3 -4-F, 4-iPr, Ph, 4- MeO-C6H4, 4-tBu, 2, 4-diMe, 2-thienyl, 2-MeO-4-Cl, 4-C1, 2-furayl, 4-F-C6H4, 2,4-diMeC6H3, 3- Me-4-F or 4-C1-C6H4.
  • the present technology is directed to compounds of Formula
  • Rl and R2 are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • any of Rl and R2 can be any of the moieties listed below in
  • the present technology is direct to compounds of Formula
  • any of Q and Rl are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • the present technology is directed to compounds of Formula
  • any of Q and Rl are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • the present technology is directed to compounds of Formula
  • any of A and Rl are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • the present technology is directed to compounds of Formula
  • any of Ql, Q2 and Rl are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • the technology is directed to compounds of Formulas (VII) or (VIII):
  • any of X and R is: C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, and amide, an amine, an ether, a thiol or a nitrile; and wherein n is an integer 1, 2, 3, 4, 5 or 6.
  • the X-R moiety represents a benzene ring fused to the n-membered ring containing the N substitution, to create a bicyclic functional group; see. e.g.. Compounds F41 through F47 below.
  • Tables 12 and 13 show a summary of selected compounds for CRC analysis.
  • Another useful compound is Compound Z95 :
  • FIGS. 20A and 20B show further results of cytokines release by hPBMC and cytotox on Compound Z95.
  • Table 17 shows screening results from another set of compounds.
  • FIG. 24 shows the results of testing done on Compound E56.
  • FIGS. 25A and 25B show further results of testing done on Compound Z96.
  • FIGS. 25A and 25B show further results of testing done on Compound Z96.
  • 26A and 26B show further results of testing done on Compound Z97.
  • Table 20 shows shows screening results from another set of compounds.
  • Table 21 shows results of testing on Compound D28.
  • FIGS. 27A and 27B show NR2F6 and LBD transient transfection, respectively, for
  • FIGS. 27C and 27D show NR2F6 and LBD transient transfection at different concentrations for different compounds. 9 compounds were tested on LBD transfected cells (40, 10, 2 and 0.5 mM, 4 replicates).
  • FIGS. 27E and 27F show toxicity of Compound D28. 9 compounds were tested for cytotoxicity on LBD transfected cells (40, 10, 2 and 0.5 pM, 4 replicates). Tox effect was found to cause lower signal compared to DMSO. Cytotoxicity normalized to DMSO is shown in FIG. 27F (0% cytotoxicity corresponds to DMSO signal, 100% - zero signal).
  • FIGS. 28A-D show the results of a cytokind release experiment for dog and human
  • Dog PBMC (1 x 106 cells/mL) were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) /without (0%) PMA + ionomycin activation.
  • the present technology is directed to compounds of Formula
  • R A is C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • exemplary but non limiting compounds are shown below:
  • the present technology is directed to compounds of Formula
  • R B is C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • exemplary but non limiting compounds are shown below:
  • the present technology is directed to compounds of Formula
  • R -R are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • exemplary but non-limiting compounds are shown below:
  • Ri and Rg is C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, or a thiol.
  • exemplary but non-limiting compounds are shown below:
  • FIGS. 29-32 show exemplary methods of formulating the compounds that have been discussed herein.
  • FIG. 31 A shows an exemplary synthesis of compounds including the following:
  • FIG. 33A and 33B show NR2F6 and LBD transient transfection for Compound E21.
  • FIGS. 34A and 34B show NR2F6 LBD transient transfection for Compound E21. 9 compounds were tested on LBD transfected cells (40, 10, 2 and 0.5 mM, 4 replicates).
  • FIGS. 34C and 34D show NR2F6 and LBD transient transfection at different concentrations for different compounds. 9 compounds were tested on LBD transfected cells (40, 10, 2 and 0.5 pM, 4 replicates). Tox effect was found to cause lower signal compared to DMSO. Cytotoxicity normalized to DMSO is shown in FIG. 34D (0% cytotoxicity corresponds to DMSO signal, 100% - zero signal). All compounds were tested at 5, 10, 25 and 50 uM in duplicates.
  • Dog PBMC (1 x 106 cells/mL) were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) /without (0%) PMA + ionomycin activation.
  • Table 23 shows the screening results of certain of the above compounds.
  • Additional compounds synthesized and found to have desirable activity include the following:
  • FIG. 37 shows exemplary methods of formulating the compounds that have been discussed herein; specifically, exemplary synthesis of compounds including the following: Compound Z160, Compound Z161, Compound Z162, Compound Z163.
  • FIGS 38A and 38B show NR2F6 and LBD transient transfection, respectively, for
  • FIGS. 39A and 39B show NR2F6 LBD transient transfection for Compound Fl .
  • 9 compounds were tested on LBD transfected cells (40, 10, 2 and 0.5 mM, 4 replicates).
  • FIGS. 39C and 39D show toxicity of NR2F6 LBD transient transfection. 9 compounds were tested for cytotoxicity on LBD transfected cells (40, 10, 2 and 0.5 pM, 4 replicates). Tox effect causes lower signal compared to DMSO. Cytotoxicity normalized to DMSO is shown in FIG. 39D (0% cytotoxicity corresponds to DMSO signal, 100% - zero signal).
  • FIGS. 40A-D show the results of cytokine release experiment for dogs and human
  • Dog PBMC (1 x 106 cells/mL) were activated by 10 ng/mL PMA + 500 ng/mL ionomycin. Data were normalized to controls with (100%) /without (0%) PMA + ionomycin activation.
  • FIG. 41 shows the general SAR strategy for testing Compound Fl and compounds related to it in structure.
  • the active molecule was divided into four domains (Domains A through D). Each domain was evaluated independently to establish SAR trends. Combinations of optimized domains evaluated additive or synergistic effect. 4 related analogs were available.
  • a compound herein has Formula (XIII):
  • n is an integer 1, 2, or 3
  • R is any other moiety mentioned in the present disclosure (e.g., C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile).
  • a compound herein has Formula (XIV):
  • X is C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol, a nitrile or any other moiety mentioned herein.
  • the present technology is directed to compounds comprising a boronate, and synthesis of such compounds.
  • FIG. 42 shows an exemplary synthesis of a boronate compound.
  • the synthesis achieved a yield of at least about 95%, at least about 90% and at least about 85%; with at least about 85% purity.
  • a regioisomer was present in the yield, in amounts of about 10 to about 20%, or about 12 to about 18%.
  • the regioisomers could be separated.
  • FIG. 42 shows the results of other exemplary syntheses of compounds comprising boronate, and the relative proportions of resultant compounds.
  • Compound P 1 Another compound found to have good activity is Compound P 1 :
  • Table 25 shows results of testing on Compound P 1.
  • FIGS. 44A and 44B show NRdF6 and LBD transient transfection of Compound P 1.
  • FIGS. 45A-D show NR2F6 LBD transient transfection for 9 different compounds, including Compound P 1.
  • FIGS. 46A and 46B show the results of the cytokine release experiment with dogs
  • FIGS. 47A and 47B show NR2F6 agonist activity and NR2F6 agonist activity
  • Compound E53 increases firefly activity in 6 times at 10 uM and appeared to show strong cytotox effect (great decreasing both renilla and firefly activity). Both Compounds Z92 and E53 will be tested on greater concentration range for confirmation on both cell line with double stable transfection (clone Fl-pGL4) and cell line with transient transfection.
  • the present technology is directed to compounds of Formula
  • R is C, H, N, O, S, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • R is H or an alkyl group.
  • the present technology is directed to compounds of Formula
  • Rl and R2 are C, H, N, O, S, a halogen, an alkyl group, a substituted alkyl group, a cyclic alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, an ester, an aldehyde, a ketone, a carboxylic acid, an amide, an amine, an ether, a thiol or a nitrile.
  • Rl and R2 are H, alkyl, phenyl, piperidine, or pyrrolidine.
  • Exemplary compounds include the following:
  • Table 26 shows activity results for two exemplary compounds, Compound Z95 and
  • FIGS. 48-51 show embodiments of a synthetic methods of formulating a compound according to the present technology.
  • FIGS. 52-55 illustrate syntheses of various compounds discussed herein.
  • FIGS. 56A and 56B show HTS activity confirmation for various compounds.
  • Compound E53 shown similar slight activity ( ⁇ 3 times firefly signal over DMSO level) at 10 uM and 50 uM. 8010-3060 increase firefly activity in 6 times at 10 uM and It seems it shown strong cytotox effect (great decreasing both renilla and firefly activity). Both Compound Z92 and Compound E53 will be further tested on greater concentration range for confirmation on both cell line with double stable transfection (clone Fl-pGL4) and cell line with transient transfection.
  • FIGS. 57 and 58 show syntheses of exemplary compositions found to be useful.
  • Table 27 shows the activity of various compounds discussed herein.

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Abstract

La présente invention concerne des modulateurs de l'activité de récepteurs nucléaires, notamment la modulation de l'activité de NR2F6 Et de NR2F6 à l'aide de composés, ainsi que la modulation immune et la modulation de l'activité de cellules souches cancéreuses par l'administration des composés décrits dans l'invention. Dans certains modes de réalisation, la présente invention concerne des procédés d'utilisation de composés à petites molécules en tant que modulateurs immuns.
PCT/US2018/062290 2017-11-21 2018-11-21 Agonistes et antagonistes à petites molécules de l'activité de nr2f6 chez des non-humains Ceased WO2019104201A1 (fr)

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US15/820,324 2017-11-21
US15/820,334 2017-11-21
US15/820,334 US20190054118A1 (en) 2016-07-18 2017-11-21 Small Molecule Agonists and Antagonists of NR2F6 Activity in Animals
US15/820,324 US11324719B2 (en) 2016-07-18 2017-11-21 Small molecule agonists and antagonists of NR2F6 activity in humans
US16/008,631 2018-06-14
US16/008,526 US11377442B2 (en) 2016-07-18 2018-06-14 Small molecule agonists and antagonists of NR2F6 activity
US16/008,631 US10472351B2 (en) 2016-07-18 2018-06-14 Small molecule agonists and antagonists of NR2F6 activity in animals
US16/008,526 2018-06-14

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KR102664292B1 (ko) * 2023-12-08 2024-05-08 한국원자력의학원 항산화 반응요소 활성제를 유효성분으로 포함하는 암 전이 억제용 약학적 조성물
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EP4265248A1 (fr) * 2022-04-22 2023-10-25 Université Paris Cité Composés induisant la production de protéines par les cellules immunitaires
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