WO2024211999A9 - Produits radiopharmaceutiques ciblés sur hsp90 extracellulaire (ehsp90) et leur utilisation - Google Patents

Produits radiopharmaceutiques ciblés sur hsp90 extracellulaire (ehsp90) et leur utilisation Download PDF

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WO2024211999A9
WO2024211999A9 PCT/CA2024/050467 CA2024050467W WO2024211999A9 WO 2024211999 A9 WO2024211999 A9 WO 2024211999A9 CA 2024050467 W CA2024050467 W CA 2024050467W WO 2024211999 A9 WO2024211999 A9 WO 2024211999A9
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compound
alkyl
group
cancer
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WO2024211999A1 (fr
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Christopher Paul Leamon
Hari Krishna R. Santhapuram
Iontcho R. Vlahov
Stuart James MAHONEY
Alexander James NIELSEN
Samuel Kunjunju KUTTY
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Fusion Pharmaceuticals Inc
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Fusion Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0453—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic

Definitions

  • Heat shock protein 90 is a molecular chaperone that regulates protein folding to ensure correct conformation and translocation and to avoid protein aggregation.
  • Many oncogenic proteins are HSP90 client proteins, such as epidermal growth factor receptor (EGFR) mutant, cyclin dependent kinase 4 (CDK4), hypoxia-inducible factor (HIF)-1a, and matrix metallopeptidase 2 (MMP2).
  • HSP90 extracellular HSP90
  • eHSP90 extracellular HSP90
  • HSP90 inhibition has been shown to have a significant direct impact on cell cycle and DNA repair mechanisms, thus offering great promise in the treatment of a wide variety of solid and hematological malignancies.
  • early clinical trials have demonstrated that certain HSP90 inhibitors exhibited limited efficacy and various side effects.
  • radiopharmaceuticals comprising a targeting moiety that specifically binds to HSP90, in particular, eHSP90
  • RLT radioligand therapy
  • Radioactive decay can cause direct physical damage (such as single or double-stranded DNA breaks) or indirect damage (such as by-stander or crossfire effects) to the biomolecules that constitute a cell.
  • Drugs that deliver radionuclides to cancer cells, i.e., radiopharmaceuticals provide a mechanism to generate DNA damage with anti-cancer therapeutic effect.
  • the present disclosure provides certain radiopharmaceuticals, specifically, small molecule-based radiopharmaceuticals targeting HSP90- overexpressing tumors and using actinium -225 ( 225 Ac), lutetium- 177 ( 177 Lu) or other suitable therapeutic radionuclides to target cancer cells to treat or ameliorate cancers such as lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.
  • actinium -225 225 Ac
  • lutetium- 177 177 Lu
  • suitable therapeutic radionuclides to target cancer cells to treat or ameliorate cancers such as lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.
  • the present disclosure provides compounds of Formula I, or a pharmaceutically acceptable salt thereof: wherein T is a targeting moiety that binds to HSP90, L is a hydrophilic space linker comprising one or more cyclic or acyclic polyhydroxy groups, and W is a chelator, wherein the compound optionally further comprises a radionuclide chelated by the chelator thereof.
  • T is a targeting moiety that binds to HSP90
  • L is a hydrophilic space linker comprising one or more cyclic or acyclic polyhydroxy groups
  • W is a chelator
  • the targeting moiety is selected from the group consisting of:
  • the compounds of this disclosure specifically bound to extracellular HSP90 (eHSP90).
  • the compounds of this disclosure have the structure of Formula II: wherein L is a hydrophilic space linker comprising one or more cyclic or acyclic polyhydroxy groups, and W is a chelator selected from the group consisting of DOTA, DOT AGA, NOTA, NOD AGA, NODASA, DTP A, TETA, EDTA, TRITA, CDTA, and DFO, wherein the compound binds to HSP90, wherein the compound optionally further comprises a radionuclide chelated by the chelator thereof.
  • Z 1 and Z 2 each are, independently, absent or a moiety selected from the group consisting an amino acid unit, and a combination thereof, in which each of R 1 and R 2 independently is H or C 1-5 alkyl;
  • Z 1 , and Z 2 are absent, and n is 1-3.
  • Z 2 is absent
  • n is 1-3.
  • At least one of Z 1 and Z 2 is an amino acid unit.
  • the amino acid unit can be formed from aspartic acid (Asp), glutamic acid (Glu), 2,4- diaminobutyric acid (Dab), 2,3-diaminopropionic acid (Dap), lysine (Lys), or arginine (Arg).
  • X is C 1-3 alkyl
  • A is nd Y is absent, C 1-5 alkoxyl, or C 2-8 polyethylene glycol, wherein indicates the attachment point to X, and indicates the attachment point to Y.
  • B is a cyclic polyhydroxy group having the structure of wherein indicates the attachment point to Y, r is 1-2, s is 3-4, and each R, independently, is OH, -CH 2 OH, -CO 2 H, -CONH 2 , NH 2 , or NHCOCH 3 , wherein B comprises at least three OH groups.
  • m is 3-4
  • p is 1-2
  • R is OH or
  • the compounds of Formulas I-IV feature that each compound comprises a radionuclide selected from the group consisting of 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 6 7 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 90 Y, 97 Ru, "Tc, " m Tc, 105 Rh, 109 Pd, m In, 117m Sn, 149 Pm, 149 Tb, 153 Sm, 166 HO, 177 LU, 186 Re, 188 Re, 198 Au, 199 AU, 201 T1, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 AC, 227 Th, and 229 Th.
  • a radionuclide selected from the group consisting of 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 6 7 Cu, 66 Ga, 67 Ga,
  • the radionuclide is selected from the group consisting of 68 Ga, 89 Zr, 90 Y, ni In, 177 LU, and 225 Ac.
  • the radionuclide is 177 Lu or 225 Ac.
  • the present disclosure also covers a pharmaceutical composition comprising one of the compounds set forth above and a pharmaceutically acceptable excipient.
  • the method of treating cancer comprises administering to the subject in need thereof a first dose of one of the compounds or the composition described above in an amount effective for radiation treatment planning, followed by administering subsequent doses of one of the compounds or the composition described above in a therapeutically effective amount.
  • the cancer is small-cell lung cancer, non-small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.
  • This disclosure also relates to any one of the compounds provided herein for use in a method of treating cancer.
  • the present disclosure relates to radiopharmaceutical compounds comprising a targeting moiety that specifically binds to HSP90, in particular, extracellular HSP90 (eHSP90).
  • eHSP90 extracellular HSP90
  • Radio-labelled targeting molecules are designed to target a protein or receptor (e.g., eHSP90) that is upregulated in a disease state and/or specific to diseased cells (e.g., tumor cells) to deliver a radioactive payload to damage and kill cells of interest.
  • Radiopharmaceuticals targeting eHSP90 provided in this disclosure can be used for treating various cancers including, but not limited to, small-cell lung cancer, non-small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, and colon cancer. Definitions
  • alkyl is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons represented as C 1-20 alkyl (e.g., C 1-6 alkyl having 1 to 6 carbons, C 1-8 alkyl having 1 to 8 carbons, C 1-10 alkyl having 1 to 10 carbons, or C 1-12 alkyl having 1 to 12 carbons), unless otherwise specified.
  • Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C 1-6 alkoxy; (2) C 1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH 2 ) or a substituted amino (i.e., -N(R N1 ) 2 , where R N1 is as defined for amino); (4) C 6-10 aryl- C 1-6 alkoxy; (5) azido;
  • R A' is selected from the group consisting of (a) C 1-20 alkyl (e.g., C 1-6 alkyl), (b) C 2-20 alkenyl (e g., C 2-6 alkenyl), (c) C 6-10 aryl, (d) hydrogen, (e) C 1-6 alk- C 6-10 aryl, (f) amino- C 1-20 alkyl, (g) polyethylene glycol of -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR’, wherein si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R’ is H or C 1-20 alkyl (e.g., C 1-6 alkyl), (b) C 2-20 alkenyl (e g
  • R G' is selected from the group consisting of (a) C 1-20 alkyl (e.g., C 1-6 alkyl), (b) C 2-20 alkenyl (e.g., C 2-6 alkenyl), (c) C 6-10 aryl, (d) hydrogen, (e) C 1-6 alk-C 6-10 aryl, (f) amino- Ci-2o alkyl, (g) polyethylene glycol of -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR’, wherein si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R’ is H or C 1-20 alkyl, and (h) amino-polyethylene glycol of
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl can be further substituted with an oxo group to afford the respective aryloyl substituent.
  • alkylene alkylidene
  • alk- alk-
  • C x-y alkyl C x-y alkylene
  • C x.y alkylidene C x.y alkylidene
  • C x-y alk- represent alkyl or alkylene groups having between x and y carbons.
  • Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C 1-6 , C 1-10 , C 2-5 , C 2-8 , C 2-10 , or C 2-20 alkyl or alkylene).
  • the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group.
  • alkenyl represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1 -propenyl, 2-propenyl, 2-methyl-1 -propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyls include both cis and trans isomers.
  • Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • alkynyl represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, 1-propynyl, and the like.
  • Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.
  • amino represents -N(R N1 ) 2 , wherein each R N1 is, independently, H, OH, NO 2 , N(R N2 ) 2 , SO 2 OR N2 , SO 2 R N2 , SOR N2 , an A-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e g., optionally substituted with an ( ⁇ -protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or
  • Amino groups can be unsubstituted amino (i.e., -NH 2 ) or substituted amino (i.e., -N(R N1 ) 2 ) groups.
  • amino is -NH 2 or -NHR N1 , wherein R N1 is, independently, OH, NO 2 , NH 2 , NR N2 2, SO 2 OR N2 , SO 2 R N2 , SOR N2 , alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e g., t-butoxycarbonylalkyl) or aryl, and each R N2 can be H, C 1-20 alkyl (e.g., C 1-6 alkyl), or C 6-10 aryl.
  • amino acid refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of -CO 2 H or a sulfo group of -SO 3 H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain).
  • amino acid used herein includes both natural amino acids and unnatural amino acids.
  • the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group.
  • Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl.
  • Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine.
  • Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C 1-6 alkoxy; (2) C 1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., -NH 2 ) or a substituted amino (i.e., -N(R N1 ) 2 , where R N1 is as defined for amino); (4) C 6-10 aryl-C 1-6 alkoxy; (5) azido; (6) halo; (7) (C 2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (11) C1.7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) -CO 2 R A' , where R A' is
  • aryl represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2- dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthranyl, phenanthrenyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1) C1.7 acyl (e.g., carboxyaldehyde); (2) C 1-20 alkyl (e.g., C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl sulfinyl -C 1-6 alkyl, amino-C 1-6 alkyl, azido-C 1-6 alkyl, (carboxyaldehyde)-
  • C1.7 acyl e.
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci- alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • acyl represents an a radical of general formula -C(O)R, where R is an alkyl or aryl group.
  • R is an alkyl or aryl group.
  • Examples of an “acyl” group include, but are not limited to, - C(O)CH 3 , C(O)C 2 H 5 , and -C(O)Ph.
  • cycloalkyl represents a monovalent saturated or unsaturated nonaromatic cyclic hydrocarbon group from three to eight carbons represented as C 3-8 cycloalkyl (e.g., C 3-5 cycloalkyl having 3 to 5 carbons, C 3-6 cycloalkyl having 3 to 6 carbons), unless otherwise specified.
  • Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle heptyl, and the like.
  • the cycloalkyl group when the cycloalkyl group includes one carbon-carbon double bond or one carbon-carbon triple bond, the cycloalkyl group can be referred to as a “cycloalkenyl” or “cycloalkynyl” group respectively.
  • exemplary cycloalkenyl and cycloalkynyl groups include cyclopentenyl, cyclohexenyl, cyclohexynyl, and the like.
  • Cycloalkyl groups can be optionally substituted with: (1) C 1-7 acyl (e.g., carboxyaldehyde); (2) C 1-20 alkyl (e.g., C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylsulfinyl- C 1-6 alkyl, amino-C 1-6 alkyl, azido-C 1-6 alkyl, (carboxyaldehyde)-C 1-6 alkyl, halo-C 1-6 alkyl (e g., perfluoroalkyl), hydroxy-C 1-6 alkyl, nitro-C 1-6 alkyl, or C 1-6 thioalkoxy-C 1-6 alkyl); (3) C 1-20 alkoxy (e.g., C 1-6 alkoxy, such as perfluoroalkoxy); (4) C 1-6 alkyl sulfinyl; (5) C 6-10 aryl; (6) amino; (7) C 1-6 al
  • each of these groups can be further substituted as described herein.
  • the alkylene group of a Ci-alkaryl or a Ci-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.
  • halo or halogen, as used herein, represents a halogen selected from bromine, chlorine, iodine, or fluorine.
  • heteroalkyl refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • C 1-20 heteroalkyl represents an alkyl group comprising one or more of nitrogen, oxygen, or sulfur in addition to 1 to 20 carbons (e.g., C 1-6 heteroalkyl having 1 to 6 carbons and one or more of nitrogen, oxygen, or sulfur, C 1-8 heteroalkyl having 1 to 8 carbons and one or more of nitrogen, oxygen, or sulfur, C 1-10 heteroalkyl having 1 to 10 carbons and one or more of nitrogen, oxygen, or sulfur, or C 1-12 heteroalkyl having 1 to 12 carbons and one or more of nitrogen, oxygen, or sulfur).
  • heteroalkyl is polyethylene glycol (PEG), wherein two more of the carbons have each been replaced by oxygen, e.g., C 2-20 polyethylene glycol (e.g., C 2-10 polyethylene glycol or C 6-8 polyethylene glycol).
  • the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heteroalkenyl and heteroalkynyl refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • the heteroalkenyl and heteroalkynyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.
  • heterocycloalkyl refers to a cycloalkyl group, as defined herein, in which one or more of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur.
  • C 1-20 heterocycloalkyl represents a cycloalkyl group comprising one or more of nitrogen, oxygen, or sulfur in addition to 1 to 20 carbons (e.g., C 1-6 heterocycloalkyl, C 1-8 heterocycloalkyl, C 2-8 heterocycloalkyl, C 1-10 heterocycloalkyl, or C 1-12 heterocycloalkyl).
  • heteroaryl represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n +2 pi electrons within the mono- or multicyclic ring system.
  • exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons.
  • heteroaiyl examples include, but are not limited to, furan, oxazole, thiophene, 1,2,3-triazole, 1,2,4-triazine, 1,2,4-triazole, 1,2,5- thiadiazole 1,1-dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4- thiadiazole, 1,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, and thiazole.
  • the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups as defined for a heterocyclyl group.
  • polyethylene glycol represents an alkoxy chain comprised of one or more monomer units, each monomer unit consisting of -OCH 2 CH 2 -.
  • Polyethyelene glycol (PEG) is also sometimes referred to as polyethylene oxide (PEO) or polyoxyethylene (POE), and these terms may be considered interchangeable for the purpose of this disclosure.
  • a polyethylene glycol may have the structure, -(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 O-, wherein si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), and each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10).
  • Polyethylene glycol may also be considered to include an amino-polyethylene glycol of - NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 -, wherein si is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each R N1 is, independently, hydrogen or optionally substituted C 1-6 alkyl.
  • isomer means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound. It is recognized that the compounds can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers, enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • stereomers depicted herein encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates.
  • Enantiomeric and stereoisomeric mixtures of compounds can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • stereoisomer refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds may exist in different tautomeric forms, all of the latter being included within the scope of the present disclosure.
  • stereomer means stereoisomers that are not mirror images of one another and are non-superimposable on one another.
  • enantiomer means each individual optically active form of a compound, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.
  • a dose of about 100 kBq/kg indicates a dose range of 100 ⁇ 10% kBq/kg, i.e., from 90 kBq/kg to 110 kBq/kg, inclusive.
  • the term “administered in combination,” “combined administration,” or “coadministered” means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient.
  • two or more agents that are administered in combination need not be administered together.
  • they are administered within 90 days (e.g., within 80, 70, 60, 50, 40, 30, 20, 10, 5, 4, 3, 2, or 1 day(s)), within 28 days (e.g., with 14, 7, 6, 5, 4, 3, 2, or 1 day(s), within 24 hours (e.g., 12, 6, 5, 4, 3, 2, or 1 hour(s), or within about 60, 30, 15, 10, 5, or 1 minute of one another.
  • the administrations of the agents are spaced sufficiently closely together such that a combinatorial effect is achieved.
  • administering includes contacting cells of said subject with the agent.
  • cancer refers to any cancer caused by the proliferation of malignant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, and lymphomas.
  • a “solid tumor cancer” is a cancer comprising an abnormal mass of tissue, e g., sarcomas, carcinomas, and lymphomas.
  • a “hematological cancer” or “liquid cancer,” as used interchangeably herein, is a cancer present in a body fluid, e.g., lymphomas and leukemias.
  • chelate refers to an organic compound or portion thereof that can be bonded to a central metal or radiometal atom at two or more points.
  • conjugate refers to a molecule that contains a chelating group or metal complex thereof, a linker group, and which optionally contains a therapeutic moiety or a targeting moiety.
  • therapeutic moiety refers to any molecule or any part of a molecule that confers a therapeutic benefit.
  • the therapeutic moiety is a protein or polypeptide, e.g., an antibody, an antigen-binding fragment thereof.
  • the therapeutic moiety is a small molecule.
  • targeting moiety refers to any molecule or any part of a molecule that binds to a given target.
  • the targeting moiety is a protein or polypeptide such as an antibody or antigen binding fragment thereof, a nanobody, an affibody, or a consensus sequence from a Fibronectin type III domain.
  • the targeting moiety is a peptide or a small molecule.
  • the compounds described herein can be asymmetric e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Examples prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4- triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual sub-combination of the members of such groups and ranges.
  • C 1-6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and O, alkyl.
  • a phrase of the form “optionally substituted X” e.g., optionally substituted alkyl
  • X is optionally substituted alkyl
  • alkyl wherein said alkyl is optionally substituted
  • the terms “decrease,” “decreased,” “increase,” “increased,” or “reduction,” “reduced,” have meanings relative to a reference level.
  • the reference level is a level as determined by the use of said method with a control in an experimental animal model or clinical trial.
  • the reference level is a level in the same subject before or at the beginning of treatment.
  • the reference level is the average level in a population not being treated by said method of treatment.
  • an “effective amount” of an agent is that amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied.
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
  • unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
  • topical administration e.g., as a cream, gel, lotion, or ointment
  • intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
  • a “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non -inflammatory in a patient.
  • Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, radioprotectants, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration.
  • excipients include, but are not limited to: ascorbic acid, histidine, phosphate buffer, butylated hydroxytoluene (BEIT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid,
  • salts represent those salts of the compounds described here that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, or allergic response.
  • Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • Compounds may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of compounds, be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines for forming basic salts. Methods for preparation of the appropriate salts are well- established in the art.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamo
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • the term “radionuclide,” refers to an atom capable of undergoing radioactive decay (e.g., 3 H, 14 C, 15 N, 18 F, 35 S, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 75 Br, 76 Br , 77 Br , 89 Zr, 86 Y, 87 Y, 90 Y, 97 RU, "TC, " m Tc, 105 Rh, 109 Pd, m In, 123 I, 124 I, 125 I, 131 I, 134 Ce, 134 La, 149 Pm, 149 Tb, 153 Sm, 166 HO, 177 LU, 186 Re, 188 Re, 198 Au, 199 Au, 203 Pb, 211 At, 212 Pb , 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, 229Th , 66 Ga, 67 Ga, 68 Ga, 82 Rb
  • radioactive nuclide may also be used to describe a radionuclide.
  • Radionuclides may be used as detection agents.
  • Exemplary radionuclides used in this disclosure include, but are not limited to, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga, 68 Ga, 82 Rb, 86 Y, 87 Y, 89 Zr, 90 Y, 97 Ru, 99 Tc, " m Tc, 105 Rh, 109 Pd, i n In, 117m Sn, 149 Pm, 149 Tb, 153 Sm, 166 Ho, 177 Lu, 186 Re, 188 Re, 198 Au, 199 Au, 2O1 T1, 203 Pb, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 225 Ac, 227 Th, and 229 Th.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • “ameliorating” may include, for example, reducing incidence of metastases, reducing tumor volume, reducing tumor vascularization and/or reducing the rate of tumor growth. “Palliating” a disease, disorder, or condition means that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • the compounds of Formula I comprise chelating moieties or chelators.
  • the chelator can be selected from the group consisting of DOTA (1,44,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTMA (lR,4R,7R-1OR)- ⁇ , ⁇ ’, ⁇ ”, ⁇ ''' -tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOT AM (1,4,7,10- tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane), DOTPA (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetra propionic acid), DO3AM-acetic acid (2-(4,7,10-tris(2- amino-2-oxoethyl)
  • the chelator is selected from DOTA, DOTA-GA, NOTA, NODA- GA, NODA-SA, DTPA, TETA, EDTA, TRITA, CDTA, and DFO, which are defined as below:
  • DOTA stands for l,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetic acid, DOTA-GA, or DOTAGA as used herein, stands for 1,4,7, 10-tetraazacyclododececane, 1- (glutaric acid)-4,7,10-triacetic acid,
  • NOTA stands for 1,4,7-triazacyclononanetriacetic acid, NODA-GA, or NODAGA as used herein, stands for 1,4,7-triazacyclononane-N-glutaric acid-N',N" -diacetic acid,
  • NODA-SA stands for 1,4,7- triazacyclononane -1-succinic acid-4, 7-diacetic acid
  • DTPA stands for diethylenetriaminepentaacetic acid
  • TETA stands for l,4,8-1l-tetraazacyclododecane-1,4,8-11-tetraacetic acid
  • EDTA stands for ethylenediamine-N,N'-tetraacetic acid
  • TRITA stands for 1,4,7,10 tetraazacyclotridecane-1,4,7,10-tetraacetic acid
  • CDTA trans- 1,2-diaminocy cl ohexane-N,N,N',N'-tetraacetic acid
  • DFO stands for the Desferal or Desferrioxamine type group of chelators
  • the chemical name of the non-limiting example is N-[5-( ⁇ 3-[5-(Acetyl-hydroxy-amino)-pentylcarbamoyl]- propionyl ⁇ -hydroxy-amino)-pentyl]-N'-(5-amino-pentyl)-N' -hydroxy-succinamide, and with the chemical structures thereof being as follows:
  • the chelator is selected from DOTA, DOTAGA, NOTA, and NODAGA.
  • radiopharmaceuticals each comprising a radionuclide.
  • suitable radionuclides include, but are not limited to, 47 Sc, 55 Co, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Ga, 67 Ga, 67 Cu, 68 Ga, 69 Er, 77 As, 82 Rb, 89 Zr, 86 Y, 87 Y, 90 Y, 97 Ru, "Tc, " m Tc, 105 Rh, 109 Pd, 111 In, 111 Ag, 121 Sn, 127 Te, 134 Ce, 134 La, 142 Pr, 143 Pr, 149 Pm, 149 Tb, 151 Pm, 159 Gd, 153 Sm, 161 Tb, 166 Dy, 166 HO, 169 Yb, 172 Tm, 175 Yb, 177 Lu, 117m Sn, 177m Sn, 186 Re, 188 Re, 188 Rd, 198 Au, 199 Au
  • the radionuclide is selected from the group consisting of 64 Cu, 67 Cu, 68 Ga, 90 Y, 111 In, 149 Tb, 153 Sm, 177 Lu, 211 At, 212 Bi, 212 Pb, 213 Bi, 223 Ra, 225 Ac, and 227 Th.
  • the radionuclide is 68 Ga, 89 Zr, 90 Y, 111 In, 177 Lu, or 225 Ac. In certain embodiments, the radionuclide is 177 Lu or 225 Ac.
  • the radionuclide used herein is a beta-emitting radionuclide such as 177 LU. In some embodiments, the radionuclide used herein is an alpha-emitting radionuclide such as 225 Ac.
  • the compounds of the present disclosure comprise a linker as shown within the structure of Formula I, wherein the linker L is a hydrophilic space linker comprising one or more cyclic or acyclic polyhydroxy groups.
  • the linker is a hydrophilic space linker comprising one or more cyclic or acyclic polyhydroxy groups, which include without limitation sugars, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, inositols, and the like.
  • the linker can be featured as wherein
  • B is a cyclic or acyclic polyhydroxy group.
  • the linker can be featured as wherein
  • amino acid unit refers to an organic moiety formed from an amino acid (e.g., a natural amino acid or an unnatural amino acid).
  • an amino acid unit is formed as shown below: where R represents an alkyl, cycloalkyl, aryl, or heteroaryl, each of which can be optionally substituted with a suitable substituent described herein; alternatively, R together with the -NH 2 group within the amino acid form a heterocycle.
  • the amino acid or amino acid unit can be in either D- or L-form (i.e., D-enantiomer or L-enantiomer).
  • an amino acid unit is formed from aspartic acid (Asp), glutamic acid (Glu), 2,4-diaminobutyric acid (Dab), 2, 3 -diaminopropionic acid (Dap), lysine (Lys), or arginine (Arg), with their structures shown below:
  • the linker can be featured as wherein
  • X is C 1-3 alkyl
  • A is absent, C 1-5 alkoxyl, or C 2-8 polyethylene glycol, wherein indicates the attachment point to X, and “#” indicates the attachment point to Y.
  • the linker can be featured a wherein
  • B is a cyclic polyhydroxy group having the structure of wherein indicates the attachment point to Y, r is 1-2, s is 3-4, and each R, independently, is OH, -CH 2 OH, -CO 2 H, - CONH 2 , NH 2 , or NHCOCH 3 , wherein B comprises at least three OH groups.
  • B is one of the following, or a stereoisomer thereof:
  • the linker can be featured as wherein
  • B is one of the following, or a stereoisomer thereof:
  • the linker can be featured wherein a representative exemplary compound is one of the following:
  • the linker can be featured a representative exemplary compound is one of the following:
  • the compounds of this disclosure have a structure of Formula I: wherein T is a targeting moiety that binds to HSP90, L is a hydrophilic space linker comprising one or more cyclic or acyclic polyhydroxy groups, and W is a chelator, wherein the compound optionally further comprises a radionuclide chelated by the chelator thereof, wherein the targeting moiety is selected from the group consisting of:
  • the compounds of this disclosure have a structure selected from one of the following Formulas (II-a), (Ill-a), (IV-a), (Il-b), (Ill-b), and (IV-b):
  • each of the variables in Formulas (Il-a), (Ill-a), (IV-a), (Il-b), (Ill-b), and (IV-b) can respectively be any of the moieties described herein for Formulas II, III, and IV, and wherein the compound optionally further comprises a radionuclide chelated by the chelator thereof.
  • a therapy (e.g., comprising a therapeutic agent) is administered to a subject.
  • the subject is a mammal, e.g., a human.
  • the subject has cancer or is at risk of developing cancer.
  • the subject may have been diagnosed with cancer.
  • the cancer may be a primary cancer or a metastatic cancer.
  • Subjects may have any stage of cancer, e.g., stage I, stage II, stage III, or stage IV with or without lymph node involvement and with or without metastases.
  • Provided compositions may prevent or reduce further growth of the cancer and/or otherwise ameliorate the cancer (e.g., prevent or reduce metastases).
  • the subject does not have cancer but has been determined to be at risk of developing cancer, e.g., because of the presence of one or more risk factors such as environmental exposure, presence of one or more genetic mutations or variants, family history, etc.
  • the subject has not been diagnosed with cancer.
  • the cancer is small-cell lung cancer, non-small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.
  • the present disclosure provides methods of using a compound of Formula I for treating clinical indications expressing HSP90, with the compound administered to a subject (e.g., a human) in an amount therapeutically effective for such treatment.
  • a subject e.g., a human
  • therapeutic combinations as disclosed herein are administered to a subject in a manner (e.g., dosing amount and timing) sufficient to cure or at least partially arrest the symptoms of the disorder and its complications.
  • a single therapy a “monotherapy”
  • an amount adequate to accomplish this purpose is defined as a “therapeutically effective amount,” an amount of a compound sufficient to substantially improve at least one symptom associated with the disease or a medical condition.
  • the “therapeutically effective amount” typically varies depending on the therapeutic. For known therapeutic agents, the relevant therapeutically effective amounts may be known to or readily determined by those of skill in the art.
  • an agent or compound that decreases, prevents, delays, suppresses, or arrests any symptom of the disease or condition would be therapeutically effective.
  • a therapeutically effective amount of an agent or compound is not required to cure a disease or condition but will provide a treatment for a disease or condition such that the onset of the disease or condition is delayed, hindered, or prevented, or the disease or condition symptoms are ameliorated, or the term of the disease or condition is changed or, for example, is less severe or recovery is accelerated in an individual.
  • a treatment may be therapeutically effective if it causes a cancer to regress or to slow the cancer’s growth.
  • the dosage regimen (e.g., amounts of each therapeutic, relative timing of therapies, etc.) that is effective for these uses may depend on the severity of the disease or condition and the weight and general state of the subject.
  • the therapeutically effective amount of a particular composition comprising a therapeutic agent applied to mammals can be determined by the person of ordinary skill in the art with consideration of individual differences in age, weight, and the condition of the mammal.
  • the dosage of these compounds can be lower than (e g., less than or equal to about 90%, 75%, 50%, 40%, 30%, 20%, 15%, 12%, 10%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of) the equivalent dose of required for a therapeutic effect of the unconjugated agent.
  • Therapeutically effective and/or optimal amounts can also be determined empirically by those of skill in the art. Thus, lower effective doses can also be determined by those of skill in the art.
  • a radiopharmaceutical or a composition e.g., a pharmaceutical composition comprising a therapeutic agent or a radiopharmaceutical
  • dose levels and pattern being selected by the treating physician.
  • the dose and administration schedule can be determined and adjusted based on the severity of the disease or condition in the subject, which may be monitored throughout the course of treatment according to the methods commonly practiced by clinicians or those described herein.
  • a radiopharmaceutical compound of this disclosure may be administered in combination with another therapeutic agent.
  • the first and second therapies may be administered sequentially or concurrently to a subject.
  • a first composition comprising a first therapeutic agent and a second composition comprising a second therapeutic agent may be administered sequentially or concurrently to a subject.
  • a composition comprising a combination of a first therapeutic agent and a second therapeutic agent may be administered to the subject.
  • the radiopharmaceutical is administered in a single dose. In some embodiments, the radiopharmaceutical is administered more than once, i.e., multiple doses.
  • the dose of each administration may be the same or different.
  • compositions are administered for radiation treatment planning or diagnostic purposes.
  • compositions may be administered to a subject in a diagnostically effective dose and/or an amount effective to determine the therapeutically effective dose.
  • a first dose of disclosed conjugate or a composition (e.g., pharmaceutical composition) thereof is administered in an amount effective for radiation treatment planning, followed administration of a combination therapy including a conjugate as disclosed herein and another therapeutic.
  • compositions comprising one or more agents (e.g., radiopharmaceuticals) can be formulated for use in accordance with disclosed methods and systems in a variety of drug delivery systems.
  • agents e.g., radiopharmaceuticals
  • One or more physiologically acceptable excipients or carriers can also be included in the composition for proper formulation. Examples of suitable formulations are found in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • suitable formulations are found in Remington ’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed., 1985.
  • Langer Science 249:1527- 1533, 1990).
  • compositions may be formulated for parenteral, intranasal, topical, oral, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment.
  • Pharmaceutical compositions can be administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application or intraarticular injection at areas affected by the vascular or cancer condition.
  • parenterally e.g., by intravenous, intramuscular, or subcutaneous injection
  • additional routes of administration include intravascular, intra-arterial, intratumor, intraperitoneal, intraventricular, intraepidural, as well as nasal, ophthalmic, intrascleral, intraorbital, rectal, topical, or aerosol inhalation administration.
  • compositions comprising include agents (e.g., compounds as disclosed herein) dissolved or suspended in an acceptable carrier, preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
  • an acceptable carrier preferably an aqueous carrier, e.g., water, buffered water, saline, or PBS, among others, e.g., for parenteral administration.
  • Compositions may contain pharmaceutically acceptable auxiliary substances to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents, or detergents, among others.
  • compositions are formulated for oral delivery; for example, compositions may contain inert ingredients such as binders or fillers for the formulation of a unit dosage form, such as a tablet or a capsule.
  • compositions are formulated for local administration; for example, compositions may contain inert ingredients such as solvents or emulsifiers for the formulation of a cream, an ointment, a gel, a paste, or an eye drop.
  • compositions may be sterilized, e.g., by conventional sterilization techniques, or sterile filtered.
  • Aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the preparations typically will be between 3 and 11, more preferably between 5 and 9 or between 6 and 8, and most preferably between 6 and 7, such as 6 to 6.5.
  • compositions in solid form are packaged in multiple single dose units, each containing a fixed amount of the above-mentioned agent or agents, such as in a sealed package of tablets or capsules.
  • compositions in solid form are packaged in a container for a flexible quantity, such as in a squeezable tube designed for a topically applicable cream or ointment.
  • Analytical HPLC-MS is performed using a Waters Acquity HPLC-MS system comprised of a Waters Acquity Binary Solvent Manager, a Waters Acquity Sample Manager, a Water Acquity Column Manager (column temperature 30 °C), a Waters Acquity Photodiode Array Detector (monitoring at 254 nm and 214 nm), a Waters Acquity TQD with electrospray ionization and a Waters Acquity BEH C18, 2.1 x 50 mm (1.7 pm) column or using a Waters UPLC-MS-Xevo TQS -Cronos system.
  • a Waters Acquity HPLC-MS system comprised of a Waters Acquity Binary Solvent Manager, a Waters Acquity Sample Manager, a Water Acquity Column Manager (column temperature 30 °C), a Waters Acquity Photodiode Array Detector (monitoring at 254 nm and
  • Preparative HPLC is performed using a Waters HPLC system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 nm and 214 nm) and a Waters XBridge Prep C18 19 x 100 mm (5 pm) column or Waters XBridge Prep Phenyl 19 x 100 mm (5 pm).
  • a Waters HPLC system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 nm and 214 nm) and a Waters XBridge Prep C18 19 x 100 mm (5 pm) column or Waters XBridge Prep Phenyl 19 x 100 mm (5 pm).
  • Preparative HPLC is performed using a Waters HPLC system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 nm and 214 nm) and a Waters XBridge Prep C18 19 x 100 mm (5 pm) column or Waters XBridge Prep Phenyl 19 x 100 mm (5 pm).
  • a Waters HPLC system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 nm and 214 nm) and a Waters XBridge Prep C18 19 x 100 mm (5 pm) column or Waters XBridge Prep Phenyl 19 x 100 mm (5 pm).
  • Actinium-225 ( 225 Ac) was supplied by the U.S. Department of Energy Isotope Program in the Office of Science for Nuclear Physics or the Canadian Nuclear Laboratories. Lutetium-177 ( 177 Lu) was received from ITM Pharma Solutions GmbH or Monrol. Indium-111 ( 111 In) was received from BWXT Medical.
  • RadioTLC was performed with Bioscan AR-2000 Imaging Scanner, carried out on iTLC- SG glass microfiber chromatography paper (Agilent Technologies, SGI0001) or iTLC-SA glass microfiber chromatography paper (Agilent Technologies, A120B12).
  • Radioactive HPLC was performed using a Waters system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 and 214 nm), a Bioscan Flow Count radiodetector (FC-3300) and a reverse phase (C18) column, or an Agilent 1260 Infinity II LC system comprised of a G711 IB Quat Pump, a G7129A Vial sampler, a G1364F analytical scale fraction collector, a G7114A variable wavelength detector (monitoring at 254 nm), a G7116A 1260 MCT column unit, a Bioscan Flow Count radiodetector (FC-3300), and a reverse phase (Cl 8) column.
  • a Waters system comprised of a Waters 1525 Binary HPLC pump, a Waters 2489 UV/Visible Detector (monitoring at 254 and 214 nm), a Bioscan Flow
  • Radiopharmaceuticals Comprising Compounds of Formula I
  • Compounds of Formula I comprise conjugates targeting HSP90, which can be radiolabeled with a radionuclide such as Indium-111 ( 111 In), Lutetium-177 ( 177 Lu), or Actinium- 225 ( 225 Ac) to form radionuclide-chelated radiopharmaceuticals.
  • a radionuclide such as Indium-111 ( 111 In), Lutetium-177 ( 177 Lu), or Actinium- 225 ( 225 Ac) to form radionuclide-chelated radiopharmaceuticals.
  • the synthesis of compounds of Formula I, or their radionuclide-chelated radiopharmaceuticals can be referred to WO 2020/205948. Below are the synthetic schemes or protocols that can be followed to synthesize the corresponding compounds.
  • Step 1 Synthesis of (9H-Fluoren-9-yl)methyl (S)-(1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl) ⁇ 5-(ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1-oxopent-4-yn-2-yl)carbamate (Intermediate 1 - B):
  • Step 2 Synthesis of (9H-Fluoren-9-yl)methyl ((S)-1-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl) ⁇ 5-(ethylcarbamoyl)-4H-1,2,4-triazol-4-yl) benzyl)piperidin-1-yl)-1-oxo-3-( 1 -(2-( 2-(2-(2- ((( 2R, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethoxy)ethyl)-1H-1, 2, 3 -triazol-4-yl)propan-2-yl) carbamate (Intermediate 1 - C):
  • Step 3 Synthesis of 4-(4-((l-((S)-2-Amino-3-(l-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(((2R,3R,4S,5S,6R)-3,4,5-trihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4- yl)propanoyl)piperidin-4-yl)methyl)phenyl)-5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4H- l,2,4-triazole-3-carboxamide (Intermediate 1 - D):
  • Step 4 Synthesis of2,2',2"-(10-(2-(((S)-1-(4-(4-(3-(2,4-Dihydroxy-5-isopropylphenyl)-5- (ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1-oxo-3-(l-(2-(2-(2-(2-(2-(2-(((( 2R, 3R, 4S, 5S, 6R)-3, 4, 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)propan-2-yl)amino)-2-oxoethyl) ⁇ 1,4, 7, 10-tetraazacyclododecane-l ,4, 7-triyl)triacetic acid (Compound A): [
  • DIPEA 0.5 ⁇ L, 2.7 ⁇ mol, 4 equiv.
  • DIPEA 0.5 ⁇ L, 2.7 ⁇ mol, 4 equiv.
  • the reaction was stirred at room temperature (22 °C) and monitored by HPLC-MS.
  • the reaction was redosed with DIPEA after 1 h and 2.5 h (1 ⁇ L, 5.4 ⁇ mol, 8 equiv. and 2 ⁇ L, 10.8 ⁇ mol, 16 equiv. additions respectively) as well as redosed at 3h 15 min with DOTA-NHS ester HPF 6 -TFA salt (0.8 mg, 0.9 ⁇ mol, 1.4 equiv.) and DIPEA (1 ⁇ L, 5.4 ⁇ mol, 8 equiv.).
  • Step 1 Synthesis of 2,3,4, 6-Tetra-O-acetyl-D-gluconic acid This compound was prepared according to the literature (O/g. Synth. 1961, 47, 79). Briefly, zinc (II) chloride (0.23 g, 1.68 mmol) was added to 3 mL of acetic anhydride and cooled on an ice/water bath. D-glucono- ⁇ -lactone (0.50 g, 2.81 mmol) was added, and the mixture stirred for 1 hour, at which point the mixture was allowed to warm to room temperature and stirred for 24 hours. 12 mL of water was added and stirring continued until the solution was homogeneous. The solution was placed in the refrigerator overnight, at which point crystals had formed.
  • Step 1 Synthesis of (2S,8S,12R,13S,14R,15R)-12,13,14,15-Tetraacetoxy-4, 7,11,18-tetraoxo-2-
  • the protected peptide was synthesized by solid-phase peptide synthesis (SPPS) on 2- chlorotritylchloride resin (Chem-Impex, 0.72 mmol/g, 139 mg, 0.1 mmol).
  • SPPS solid-phase peptide synthesis
  • Fmoc-Dap(alloc)-OH 205 mg, 0.50 mmol was dissolved in DMF (4 mL) with potassium iodide (16 mg, 0.1 mmol) and DIPEA (174 ⁇ L, 1.0 mmol). The resulting solution was combined with the resin and stirred at room temperature overnight. Fmoc deprotection was performed for 5 and 15 minutes with 20% piperidine in DMF.
  • 2,3,4,5,6-Penta-O-acetyl-D-gluconic acid (243 mg, 0.6 mmol) was then coupled with 0.6 mmol HATU and 1.2 mmol DIPEA in DMF for 1.5 hours. Couplings were monitored by Kaiser test. After the final coupling, the resin was washed thoroughly with DCM. Cleavage from resin was performed with 20% HFIP in DCM (5 mL) for 30 minutes. The resin was drained and washed with DCM (2 mL), and the combined washings were concentrated under a stream of air.
  • Step 2' Synthesis of (2R,3R,4S,5R,9S,15S,19R,20S,21R,22R)-9-(4-(4-(3-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidine-1-carbonyl)- 6,11, 14, 18-tetraoxo-15-(2-(2-(4, 7, 10-tris(2-(tert-butoxy)-2-oxoethyl)-1, 4, 7, 10- tetraazacyclododecan-1-yl)acetamido)acetamido)-7,10, 13, 17-tetraazatricosane- 1,2,3,4,5,19,20,21,22,23-decayl decaacetate (Intermediate 4-C):
  • Step 3 Synthesis of (2R,3R,4S,5R,9S,15S,19R,20S,21R,22R)-9-(4-(4-(3-(2,4-Dihydroxy-5- isopropylphenyl)-5-(ethylcarbamoyl)-4H-1, 2, 4-triazol-4-yl)benzyl)piperidine-1 -carbonyl)- 6,1 J, 14, 18-tetraoxo-15-(2-(2-(4, 7, 10-tris(2-(tert-butoxy)-2-oxoethyl)-1, 4, 7, 10- tetraazacyclododecan-1-yl)acetamido)acetamido)-7,10, 13, 17-tetraazatricosane- 1,2,3,4,5,19,20,21,22,23-decayl decaacetate (Intermediate 4-D):
  • Step 4 Synthesis of 2,2',2''-(10-((7S,13S,17R,18S,19R,20R)-13-(4-(4-(3-(2,4-Dihydroxy-5- isopropylphenyl)-5-(ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidine-1-carbonyl)- 17,18,19,20, 21-pentahydroxy-2, 5, 8,11,16-pentaoxo- 7-( ((2R, 3S, 4R, 5R) -2, 3, 4, 5, 6- pentahydroxyhexanamido)methyl)-3, 6,9, 12, 15-pentaazahenicosyl)-1, 4, 7,10- tetraazacyclododecane-1 ,4, 7-triyl)triacetic acid (Compound C):
  • the protected peptide was synthesized by solid-phase peptide synthesis (SPPS) on 2- chlorotritylchloride resin (Chem-Impex, 0.72 mmol/g, 139 mg, 0.1 mmol).
  • SPPS solid-phase peptide synthesis
  • Fmoc-Dap(Cbz)-OH 230 mg, 0.5 mmol was dissolved in DMF (4 mL) with potassium iodide (16 mg, 0.1 mmol) and DIPEA (174 LIL. 1.0 mmol). Fmoc deprotection was performed for 5 and 15 minutes with 20% piperidine in DMF.
  • Step 2 Synthesis of tri-tert-Butyl 2,2',2"-(10-(6-(4-(4-(3-(2,4-bis(benzyloxy)-5-isopropylphenyl)- 5-(ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidine-1-carbonyl)-3,8,ll-trioxo-1-phenyl- 2-oxa-4, 7,10-triazadodecan-12-yl)-1,4, 7,10-tetraazacyclododecane-1,4, 7-triyl)(S)-triacetate (Intermediate 5-B):
  • Step 3 Synthesis of Tri-tert-butyl 2,2’,2"-(10-(2-((2-((3-amino-1-(4-(4-(3-(2,4-dihydroxy-5- isopropylphenyl)-5-(ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-1-oxopropan- 2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7-triyl)(S) ⁇ triacetate (Intermediate 5-C):
  • Step 4 Synthesis of (2R,3R,4S,5R)-6-(((S)-3-(4-(4-(3-(2,4-Dihydroxy-5-isopropylphenyl)-5- (ethylcarbamoyl)-4H-1,2,4-triazol-4-yl)benzyl)piperidin-1-yl)-3-oxo-2-(2-(2-(4, 7,10-tris(2-(tert- butoxy)-2-oxoethyl)- 1 , 4, 7, 10-tetraazacyclododecan-1-yl)acetamido)acetamido)propyl)amino)-6- oxohexane-1 ,2,3,4, 5-pentayl pentaacetate (Intermediate 5-D):
  • Step 5 Synthesis of 2,2',2"-(10-(2-((2-(((S)-1-(4-(4-(3-(2,4-Dihydroxy-5-isopropylphenyl)-5- (ethylcarbamoyl)-4H-l ,2, 4-triazol-4-yl)benzyl)piperidin-1-yl)-1-oxo-3-((2R, 3S, 4R,5R)-2, 3, 4, 5, 6- pentahydroxyhexanamido)propan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-1, 4, 7,10- tetraazacyclododecane-1 ,4, 7-triyl)triacetic acid (Compound D):
  • Step 1 Synthesis of 4-(4-((l-Acetylpiperidin-4-yl)methyl)phenyl)-N-(2-aminoethhours5-(2,4- bis(benzyloxy)-5-isopropylphenyl)-4H-1,2,4-triazole-3-carboxamide
  • Intermediate 6-B To a 20 mL scintillation vial with a stir bar was added ((2R,3S,4R,5R)-2,3,4,5-tetraacetoxy-6- azidohexanoyl)glycine (Intermediate 6-A, synthesized using in-house protocol), (20.0 mg, 0.04 mmol, 1 equiv.) and 3 mL DMF.
  • reaction mixture was cooled to 0 °C and DIPEA, (39.42 ⁇ L, 29.25 mg, 0.22 mmol, 4 equiv.), followed by HBTU, (19.3 mg, 0.05 mmol, 1.1 equiv.) was added and stirred for 20 min at 0 °C.
  • Step 2 Synthesis of 4-(4-((l-(((2R,3S,4R,5R)-6-Azido-2, 3,4,5- tetrahydroxyhexanoyl)glycyl)piperidin-4-yl)methyl)phenyl)-5-(2,4-bis(benzyloxy)-5- isopropylphenyl)-N-ethyl-4H-1,2,4-triazole-3-carboxamide (Intermediate 6-C): To a 20 mL scintillation vial containing Intermediate 6-B (11.5 mg, 10.73 pmol, 1 equiv.) was added 2 mL of methanol followed by potassium carbonate (6.0 mg, 0.04 mmol, 4 equiv.).
  • Step 3 Synthesis of 4-(4-((l-(((2R,3S,4R,5R)-6-Amino-2, 3,4,5- tetrahydroxyhexanoyl)glycyl)piperidin-4-yl)methyl)phenyl) -5-( 2, 4-dihydroxy-5- isopropylphenyl)-N-ethyl-4H-1,2,4-triazole-3-carboxamide
  • Intermediate 6-D To a flask containing Intermediate 6-C (9.7 mg, 7.34 pmol, 1 equiv.), methanol (3.5 mL) was added followed by 10% Pd/C (3.9 mg, 3.67 pmol, 0.5 equiv.) at room temperature.
  • the reaction mixture was degassed under vacuum and subjected to hydrogen gas via a balloon.
  • the reaction stirred overnight and was monitored by HPLC-MS. After stirring overnight, the reaction was incomplete, so additional Pd/C (6 mg) was added, and the reaction mixture subjected again to hydrogen gas as above.
  • the reaction was stopped after 25 hours, filtered through Acrodisc One (0.2 pm PTFE) syringe filter and the solvent evaporated under vacuum to give the crude Intermediate 6-D (12 mg, quantitative, purity: 52%) as colorless film.
  • Step 4 2,2', 2 "-( I0-( 2-((4-((2-(4-(4-((1 -Acetylpiperidin-4-yl)methyl)phenyl) -5 -(2, 4-dihydroxy-5- isopropylphenyl)-4H-1, 2,4-triazole-3-carboxamido)ethyl)carbamoyl)benzyl)amino)-2-oxoethyl)- 1 ,4, 7, 10-tetraazacyclododecane-1 ,4, 7-triyl)triacetic acid (Compound E): To a vial containing Intermediate 6-D (5.1 mg, 5.9 pmol, 1 equiv.) was added 1.5 ml DMF, followed by 2,2',2"-(10- (2 -((2, 5-Dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)- 1,4, 7, 10-tetraazacyclododecane
  • HSP90 binding is determined using a cell-free binding affinity assay, where human recombinant HSP90 protein is coated onto a Reacti-Bind® microtiter plate. Plates are incubated at 4 °C overnight and then washed 3 times with cold PBS containing 0.05% Tween-20 (PBS-T). Plates are equilibrated to room temperature, blocked for 1 hour on ice with PBS-T containing 0.2% gelatin, followed by 3 washes with PBS-T.
  • Radiolabeled (Lu- 177) conjugates are incubated in duplicate in the absence (total binding) or presence (nonspecific binding) of unlabeled conjugate, and incubated at 37 °C for 1 hour with gentle shaking. Wells are then rinsed three times with PBS-T, and stripped with a solution of 20 mM sodium acetate, pH 3.0 for up to 20 minutes at room temperature, followed by neutralization with an equal amount of 0. IN NaOH solution. Samples are transferred into gamma counting tubes and analyzed for Lu-177 content by gamma counter. Results are plotted relative to molar concentration of labeled conjugate, where specific binding affinity (Kd) is calculated using Graph Pad Prism.
  • Binding affinity (Kd) results are summarized in Table 3, where 0 nM ⁇ A ⁇ 3 nM, and B > 3 nM. [130] Table 3. Binding affinities (Kd) of selected compounds to recombinant Hsp90 ⁇ or ⁇ isoforms
  • Example 4 Biodistribution Studies of Radiopharmaceuticals Comprising Compounds of Formula I [131]
  • HSP90 expressing NCI-H460 tumor-bearing mice will be evaluated to determine the in vivo efficacy of the compounds of Formula I.
  • Mice implanted with HSP90 expressing NCI-H460 xenograft tumors will be treated with various concentrations and doses of Ac-225 labelled HSP90 targeting conjugates (ranging from 0.1 to 3 pCi of activity) of Formula I administered intravenously via tail vein injection to evaluate in vivo efficacy.
  • Tumor measurements will be taken 2-3 times per week for at least 28 days with vernier calipers in two dimensions to evaluate tumor growth, and body weight, along with overall body condition and general behaviour will be assessed daily.

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Abstract

L'invention concerne des composés radiopharmaceutiques comprenant une fraction de ciblage qui se lie spécifiquement à HSP90, en particulier, HSP90 extracellulaire, un lieur unique et un chélateur. L'invention concerne également des compositions pharmaceutiques et des méthodes de traitement du cancer avec celles-ci.
PCT/CA2024/050467 2023-04-14 2024-04-12 Produits radiopharmaceutiques ciblés sur hsp90 extracellulaire (ehsp90) et leur utilisation Ceased WO2024211999A1 (fr)

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EP3773670A4 (fr) * 2018-04-05 2022-03-09 Tarveda Therapeutics, Inc. Conjugués ciblant la hsp90 et formulations associées
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