EP4598516A2 - N-acétylcystéine ciblant les mitochondries et analogues - Google Patents

N-acétylcystéine ciblant les mitochondries et analogues

Info

Publication number
EP4598516A2
EP4598516A2 EP23875746.2A EP23875746A EP4598516A2 EP 4598516 A2 EP4598516 A2 EP 4598516A2 EP 23875746 A EP23875746 A EP 23875746A EP 4598516 A2 EP4598516 A2 EP 4598516A2
Authority
EP
European Patent Office
Prior art keywords
compound
nac
pharmaceutically acceptable
acceptable salt
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23875746.2A
Other languages
German (de)
English (en)
Inventor
Balaraman Kalyanaraman
Micael Joel Hardy
Gang Cheng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aix Marseille Universite
Medical College of Wisconsin
Original Assignee
Aix Marseille Universite
Medical College of Wisconsin
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aix Marseille Universite, Medical College of Wisconsin filed Critical Aix Marseille Universite
Publication of EP4598516A2 publication Critical patent/EP4598516A2/fr
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5456—Arylalkanephosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma.
  • NAC is not readily bioavailable and is used in high concentrations.
  • NAC N-acetylcysteine
  • SUMMARY OF THE INVENTION [0005] Disclosed herein are modified N-acetylcysteine (NAC) compounds, pharmaceutical compositions comprising the compounds, kits, and methods of use thereof.
  • the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof
  • W is NH, O, or S, MCW C2267 Attorney Docket No. 650053.01008
  • L is C1-C20 alkylene, C2-C20 alkenylene, L1-R A -L2, or amino acid
  • L1 and L2 are each independently absent or C1-C10 alkylene
  • R A is –(CH2CH2O)q–, arylene, or cycloalkylene
  • q is 1-20
  • X is a counterion
  • Y at each occurrence is independently CF 3 , Me, Cl, OMe, C(O)CH 3 , NO 2 , N(Me) 2 , or OH
  • m at each occurrence is independently 0, 1, 2, 3, 4, or 5, provided that the compound is not (R)-2-acetamido-3-mercapto-N- methylpropanamide or (R)-2-acetamido-3-
  • the compound, or a pharmaceutically acceptable salt thereof is isotopically labeled.
  • the compound can be 13 C labeled.
  • the present disclosure provides a pharmaceutical composition.
  • the pharmaceutical composition comprises the compound as disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure provides a method of treating cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of enhancing CAT-T cell therapy in a subject in need thereof.
  • the method comprises administering to the subject an effective amount of the compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of analyzing a sample. The method comprises contacting the sample with an isotopically labeled compound (e.g., a 13 C labeled compound) as described herein, or a pharmaceutically acceptable salt thereof, thereby producing a labeled sample, and analyzing the labeled sample.
  • an isotopically labeled compound e.g., a 13 C labeled compound
  • a pharmaceutically acceptable salt thereof e.g., a pharmaceutically acceptable salt thereof
  • FIGS. 2A-2B show effects of NAC and Mito 10 -NAC on the proliferation of cells derived from various cancers.
  • FIG. 2A shows the effects of NAC and Mito10-NAC on the MCW C2267 Attorney Docket No. 650053.01008 proliferation of MiaPaCa-2 cells were monitored in the IncuCyte Live-Cell Analysis system.
  • the IncuCyte analyzer provides real-time updates on cell confluence, based on segmentation of high definition-phase contrast images. Representative cell images were shown as segmentation mask illustrated in brown when control cells reached 90% confluence (vertical solid black line).
  • FIG.2B shows the same proliferation monitoring methods were used for all cell lines as indicated.
  • FIG. 3A demonstrates comparisons of mitochondria-targeted drugs and the corresponding parent compounds on cell proliferation inhibitions in human pancreatic cancer (MiaPaCa-2) cells. The effects of mitochondria-targeted drugs and their parental compounds on the proliferation of MiaPaCa-2 cells were monitored in the IncuCyte Live-Cell Analysis system.
  • FIG. 3B shows the comparison of IC50 values between Mito-Met and metformin, between Mito-LND and LND, between Mito-HNK and HNK, and between Mito-ATO and ATO.
  • FIGS. 4A-4B show effects of Mito 10 -NAC analogs on the proliferation of human pancreatic cancer (MiaPaCa-2) cells.
  • FIG.4A shows the effects of Mito10-NAC-SMe, Mito10- PEG-NAC, NAC-SMe, and NAC amide on the proliferation of MiaPaCa-2 cells were monitored in the IncuCyte Live-Cell Analysis system.
  • the IncuCyte analyzer provides real- time updates on cell confluence, based on segmentation of high definition-phase contrast images. Representative cell images were shown as segmentation mask illustrated in brown when control cells reached 90% confluence (vertical solid black line).
  • FIG.4B shows the IC 50 values were determined at the point at which control cells reached ⁇ 90% confluence. Relative cell confluence (control is taken as 100%) is plotted against concentration.
  • FIGS. 5A-5B show effects of NAC and Mito10-NAC on intracellular ATP levels and cell death in human pancreatic cancer (MiaPaCa-2) cells.
  • FIG.5A shows effects of NAC and Mito10-NAC on the intracellular ATP level.
  • MiaPaCa-2 cells were treated with NAC or Mito10- MCW C2267 Attorney Docket No. 650053.01008 NAC for 24 h, and concentration-dependent inhibition of intracellular ATP level was measured.
  • FIGS. 5B demonstrates the SYTOX Green assay monitoring the cytotoxicity of NAC and Mito10-NAC in MiaPaCa-2 cells.
  • MiaPaCa-2 cells were treated with NAC and Mito10-NAC at the indicated concentrations (IC 50 values from FIGS. 6A-6B) for 24 h and 48 h.
  • Cell death with strong green fluorescence intensity was monitored with the IncuCyte Live-Cell Analysis system by SYTOX Green staining.
  • FIG.6A shows effects of NAC and Mito 10 -NAC on intact cell mitochondria oxygen consumption.
  • MiaPaCa-2 cells were treated with NAC or Mito10-NAC for 24 h, and concentration-dependent inhibition of mitochondrial respiration (OCR) in intact MiaPaCa-2 cells was measured.
  • OCR mitochondrial respiration
  • FIG.6B demonstrates effects of NAC and Mito 10 -NAC on oxygen consumption by mitochondrial complex I.
  • Dose-dependent effects of NAC or Mito10-NAC on complex I-dependent oxygen consumption were measured in permeabilized MiaPaCa-2 cells by direct injection with NAC or Mito10-NAC as indicated.
  • Mitochondrial complex I activities were monitored by a Seahorse XF-96 Extracellular Flux Analyzer. Then, Rotenone (complex I inhibitor) was acutely added. The mitochondrial complex I-dependent oxygen consumption was shown and calculated as rotenone inhibitable OCR.
  • FIGS. 7A-7F demonstrate the effects of Mito10-NAC in combination with NAC or AZD3965 on inhibition of cell proliferation in human pancreatic cancer (MiaPaCa-2) cells.
  • MiaPaCa-2 cells were treated with Mito10-NAC (as indicated) independently or in combination with NAC (FIGS.7A and 7C) or AZD3965 (FIGS 7B and 7D), and cell growth was monitored continuously.
  • FIGS.8A-8B show effects of NAC and Mito10-NAC on the proliferation of melanoma cancer (UACC-62) cells.
  • FIG. 8A shows the effects of NAC and Mito 10 -NAC on the proliferation of UACC-62 cells were monitored in the IncuCyte Live-Cell Analysis system.
  • the IncuCyte analyzer provides real-time updates on cell confluence, based on segmentation of high definition-phase contrast images. Representative cell images were shown as segmentation mask illustrated in brown when control cells reached 90% confluence (vertical solid black line).
  • FIG.8B shows the IC50 values were determined at the point at which control cells reached ⁇ 90% confluence. Relative cell confluence (control is taken as 100%) is plotted against concentration. Dashed lines represent the fitting curves used to determine the IC50 values as indicated. Data shown are the mean ⁇ SD.
  • FIG. 9 demonstrates effects of Mito-NAC on the proliferation of pancreatic cancer (MiaPaCa-2) cells with different treatment schedules. The effects of Mito-NAC on the proliferation of MiaPaCa-2 cells were monitored in the IncuCyte Live-Cell Analysis system. MiaPaCa-2 cells were treated with Mito-NAC either only once at the beginning of the experiment or received a fresh treatment every 48 h as indicated.
  • a compound should be interpreted to mean “one or more compounds” unless the context clearly dictates otherwise.
  • the term “plurality” means “two or more.” [0025] As used herein, “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context MCW C2267 Attorney Docket No. 650053.01008 in which they are used.
  • alkyl as used herein, means a straight or branched chain saturated hydrocarbon.
  • the alkyl can be a ⁇ 1-4 alkyl.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkylene as used herein, means a divalent group derived from a straight or branched chain saturated hydrocarbon.
  • alkylene examples include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and CH2CH(CH3)CH(CH3)CH2-.
  • alkene as used herein, means an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched MCW C2267 Attorney Docket No. 650053.01008 group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively.
  • alkenylene as used herein, means a divalent group derived from a straight or branched alkene, which attaches to the parent molecule at two different carbon atoms.
  • aryl as used herein, means a carbocyclic aromatic group (e.g., phenyl or a bicyclic aryl).
  • aryl includes polycyclic ring systems having one or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls or cycloalkenyls.
  • a bicyclic aryl can be a phenyl fused to a cycloalkyl moiety.
  • aryl include naphthyl, dihydronaphthalenyl, tetrahydronaphthalenes, indanyl, or indenyl.
  • the aryl e.g., phenyl and bicyclic aryls
  • arylene as used herein, means a divalent group derived from an aryl as described herein, which attaches to the parent molecule at two different ring carbon atoms.
  • arylene includes, but are not limited to, phenylene, which is a divalent group derived from benzene and attaches to the parent molecule at two different ring carbon atoms (e.g., at 1,2-, 1,3-, or 1,4-positions).
  • cycloalkyl as used herein, means a monovalent group derived from an all- carbon ring system containing zero heteroatoms as ring atoms, and zero double bonds.
  • the all- carbon ring system can be a monocyclic, bicylic, or tricyclic ring system, and can be a fused ring system, a bridged ring system, or a spiro ring system, or combinations thereof.
  • cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and .
  • the cycloalkyl groups described herein can be appended to the parent through any substitutable carbon atom.
  • cycloalkylene as used herein, means a divalent group derived from an all- carbon ring system containing zero heteroatoms as ring atoms and zero double bonds, which attaches to the parent molecule at two different ring carbons atoms.
  • the all-carbon ring system can be a monocyclic, bicylic, or tricyclic ring system, and can be a fused ring system, a bridged ring system, or a spiro ring system.
  • Representative examples of cycloalkylene include, but are MCW C2267 Attorney Docket No. 650053.01008 not limited to, those derived from C 3-10 rings, .
  • term "halogen” or “halo” means a chlorine, bromine, iodine, or fluorine atom.
  • C C 4 alkyl
  • C3-6cycloalkyl C1-4alkylene
  • C1-C4 alkyl or “C1-4alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).
  • substituents are described as being independently selected from a group, each substituent is selected independent of the other. Each substituent, therefore, may be identical to or different from the other substituent(s).
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, regioisomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
  • the compound disclosed herein may exist as a regioisomer or a mixture of regioisomers.
  • pharmaceutically acceptable salt thereof means a salt prepared by combining a compound of formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), and (I-f) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts”.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids
  • organic acids such as ace
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2- hydroxyethanesulfonate, sufanilate, cyclohexylaminos
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C 1 -C 6 ) halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., MCW C2267 Attorney Docket No.
  • long chain halides e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides
  • arylalkyl halides e.g., benzyl and phenethyl bromides
  • isotopically labelled refers to compounds of Formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), and (I-f) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • Certain isotopically labelled compounds of Formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), and (I- f), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically labeled compounds of Formulae (I), (I-a), (I-b), (I-c), (I-d), (I-e), and (I-f) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically labeled reagents in place of the non-labeled reagent previously employed.
  • Site specific substitution of atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature can be regarded as a substituent of a compound of the present disclosure.
  • a sample of a compound having such an isotope as a substituent has at least 50% isotope incorporation at the labelled position(s).
  • concentration of such isotopes e.g., deuterium, may be defined by the isotopic enrichment factor.
  • isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a substituent in a compound of this invention is denoted deuterium
  • such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium MCW C2267 Attorney Docket No.
  • the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein ; MCW C2267 Attorney Docket No. 650053.01008 R 2 is H or C1-C4 alkyl; W is NH, O, or S, L is C1-C20 alkylene, C2-C20 alkenylene, L1-R A -L2, or amino acid; L 1 and L 2 are each independently absent or C 1 -C 10 alkylene; R A is –(CH2CH2O)q–, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently CF 3 , Me, Cl, OMe, C(O)CH 3 , NO 2 , N(Me) 2 , or OH; m at each occurrence is independently 0, 1, 2, 3, 4, or 5, provided that the compound is not (R)-2-acetamido-3-
  • X is F, Cl, Br, or I. In some embodiments, X is Br. In some embodiments, X is 2,2,2-trifluoroacetate or acetate.
  • R 1 is H or C 1 -C 4 alkyl.
  • R 2 is H. In some embodiments, W is NH or O. In some embodiments, R 2 is H and W is NH or O.
  • L is C1-C20 alkylene. In some embodiments, L is L1-R A -L2.
  • L is L 1 -R A -L 2 and R A is –(CH 2 CH 2 O) q –.
  • L is L 1 - R A -L2 and R A is arylene.
  • L is L1-R A -L2 and R A is cycloalkylene.
  • m is 0 or 1.
  • Y at each occurrence is independently CF3, Me, Cl, or OMe.
  • m is 1 and Y at each occurrence is independently CF 3 , Me, Cl, OMe.
  • R 2 is methyl.
  • R 1 is and R 2 is methyl.
  • R 1 is , R 2 is methyl, W is NH, and L is C 1 -C 20 MCW C2267 Attorney Docket No. 650053.01008 alkylene.
  • m is 0 or 1 and X is Br in compound of formula (I) or (I-a), or a pharmaceutically acceptable salt thereof. In some embodiments, m is 0 and X is Br.
  • n is 1, X is Br, and Y at each occurrence is independently Me, OMe, Cl, or CF3.
  • the , wherein n is 1-20.
  • n is 6, 8, 10, 12, 14, or 16.
  • In 10 and the compound .
  • n is 12 and the compound is MCW C2267 Attorney Docket No. 650053.01008 is the compound , wherein n is 1-20.
  • n is 6, 8, 10, 12, 14, or 16.
  • m is 1, X is Br, and Y is OMe. In some embodiments, the , wherein n is 1-20.
  • R 1 is H or C1-C4 alkyl
  • R 2 is H
  • W is NH or O
  • the compound has a structure of formula (I-c), (I-d), or (I-e) d), wherein t
  • R 1 is methyl in the compound of formula (I-c), or a pharmaceutically acceptable salt thereof.
  • the compound is t MCW C2267 Attorney Docket No. 650053.01008
  • R 1 is methyl in the compound of formula (I-d), or a pharmaceutically acceptable salt thereof.
  • the compound is .
  • u is 3, 4, 5, or 6.
  • R 1 is methyl in the compound of formula (I-e), or a salt thereof.
  • the compound is .
  • v is 3, 4, 5, or 6.
  • formula (I) may be selected from the group consisting of MCW C2267 Attorney Docket No. 650053.01008 [0072]
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is isotopically labeled.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof is 13 C labeled.
  • the 13 C labeled compound of formula (I), or a pharmaceutically acceptable salt thereof has a structure of formula (I-f) f).
  • n is 1-20.
  • n is 6, 8, 10, 12, 14, or 16. as described herein may have an isotopic enrichment factor for each designated 13 C atom of at least 5, at least 10, at least 20, at least 50, or at least 90.
  • Pharmaceutical Compositions [0078] Another aspect of the disclosure provides a pharmaceutical composition.
  • the pharmaceutical composition comprises the compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may include the compound in a range of about 0.1 to 2000 mg.
  • the pharmaceutical composition may include the compound in a range of from about 0.5 to 500 mg. In some embodiments, the pharmaceutical composition may include the compound in a range of from about 1 to 100 mg. The pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.1 to about 1000 mg/kg body weight. In some embodiments, the pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.5 to about 500 mg/kg body weight. In some embodiments, the pharmaceutical composition may be administered to provide the compound at a daily dose of about 50 to about 100 mg/kg body weight. In some embodiments, after the pharmaceutical composition is administered to a subject (e.g., after MCW C2267 Attorney Docket No.
  • the concentration of the compound at the site of action may be within a concentration range bounded by end-points selected from 0.001 ⁇ M, 0.005 ⁇ M, 0.01 ⁇ M, 0.5 ⁇ M, 0.1 ⁇ M, 1.0 ⁇ M, 10 ⁇ M, and 100 ⁇ M (e.g., 0.1 ⁇ M - 1.0 ⁇ M).
  • the compounds may be formulated as a pharmaceutical composition that includes a carrier.
  • the carrier may be selected from the group consisting of proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste.
  • the compounds may be formulated as a pharmaceutical composition that includes one or more binding agents, filling agents, lubricating agents, suspending agents, sweeteners, flavoring agents, preservatives, buffers, wetting agents, disintegrants, and effervescent agents.
  • Filling agents may include lactose monohydrate, lactose anhydrous, and various starches;
  • binding agents are various celluloses and cross-linked polyvinylpyrrolidone, microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, and silicified microcrystalline cellulose (ProSolv SMCCTM).
  • Suitable lubricants may include colloidal silicon dioxide, such as Aerosil®200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • colloidal silicon dioxide such as Aerosil®200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel.
  • sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame.
  • flavoring agents are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
  • preservatives may include potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride.
  • Suitable diluents may include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and mixtures of any of the foregoing.
  • diluents include microcrystalline cellulose, such as Avicel® PH101 and Avicel® PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®; mannitol; starch; sorbitol; sucrose; and glucose.
  • Suitable disintegrants include lightly crosslinked polyvinyl pyrrolidone, corn starch, potato starch, maize starch, and modified starches, croscarmellose sodium, cross-povidone, sodium starch glycolate, and mixtures thereof.
  • compositions comprising the compounds may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.
  • Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the pharmaceutical compositions are in some embodiments applied as a topical ointment or cream.
  • the compound When formulated in an ointment, the compound may be employed with either a paraffinic or a water-miscible ointment base.
  • the compound may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • Pharmaceutical compositions adapted for topical administration to the eye include eye drops where the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. MCW C2267 Attorney Docket No. 650053.01008
  • Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas.
  • compositions adapted for nasal administration where the carrier is a solid include a coarse powder having a particle size (e.g., in the range 20 to 500 microns) which is administered in the manner in which snuff is taken (i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose).
  • Suitable formulations where the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical compositions adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols, nebulizers or insufflators.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tableting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying MCW C2267 Attorney Docket No.
  • 650053.01008 agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol
  • preservatives for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
  • the disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered with additional therapeutic agents, optionally in combination, in order to treat cancers.
  • one or more additional therapeutic agents are administered with the disclosed compounds or with pharmaceutical compositions comprising the disclosed compounds, where the additional therapeutic agent is administered prior to, concurrently with, or after administering the disclosed compounds or the pharmaceutical compositions comprising the disclosed compounds.
  • the disclosed pharmaceutical compositions are formulated to comprise the disclosed compounds and further to comprise one or more additional therapeutic agents, for example, one or more additional therapeutic agents for treating cancers.
  • NAC neuropeptide acetaminophen or Tylenol
  • NAC also has been used as a direct scavenger of reactive oxygen species (hydrogen peroxide, in particular) and as an antioxidant in cancer biology and immuno-oncology.
  • NAC is frequently used as an antioxidant drug in studies employing tumor cells, immune cells, and preclinical mouse models. In both in vitro and in vivo studies, NAC is used in high concentrations as its bioavailability is relatively low. Reports indicate that the effect of NAC is cancer cell dependent and stage specific. NAC is membrane-permeant and crosses the blood– brain barrier depending on the dose and administration. The effects of NAC are attributed to its thiol modulatory role in cells.
  • the present disclosure compared the relative antiproliferative potencies of NAC, Mito10-NAC, and their methylated analogs in several cancer cells.
  • the present disclosure showed that Mito 10 -NAC is nearly 1,500–2,000 times more potent than NAC, and that methylation of the free sulfhydryl group enhanced its antiproliferative effect (the IC 50 for Mito 10 -MeNAC is 1.9 ⁇ M compared with 9.6 ⁇ M for Mito10-NAC), indicating that the antiproliferative effect is not related to the antioxidant or radical scavenging mechanism.
  • the present disclosure demonstrates the antiproliferative effects of the mitochondria-targeted compounds as described herein in cancer cells.
  • a therapeutically effective amount of the compounds as disclosed herein may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the disclosed compounds to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds as disclosed herein are reduced as compared with known compounds and are outweighed by the therapeutically beneficial effects.
  • MCW C2267 Attorney Docket No. 650053.01008
  • composition and methods of the present disclosure can be utilized to treat cancers that manifest solid tumors such as pancreatic cancer, breast cancer, colon cancer, lung cancer, prostate cancer, thyroid cancer, ovarian cancer, skin cancer, and the like.
  • the composition and methods of the present disclosure can also be utilized to treat non-solid tumor cancers such as non-Hodgkin's lymphoma, leukemia and the like.
  • non-solid tumor cancers such as non-Hodgkin's lymphoma, leukemia and the like.
  • subject refers mammals, non-mammals, and/or cells.
  • the term “treat” or “treating” refers to the management and care of a subject for the purpose of combating the disease, condition, or disorder. Treating includes the administration of a compound of the present disclosure to inhibit, ameliorate and/or improve the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • administering refers to any means for introducing the compounds as disclosed herein into the body, preferably into the systemic circulation. Examples include but are not limited to oral, buccal, sublingual, pulmonary, transdermal, transmucosal, as well as subcutaneous, intraperitoneal, intravenous, and intramuscular injection.
  • the compounds utilized in the methods disclosed herein may be administered in conventional dosage forms prepared by combining the active ingredient with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the subject may be administered a dose of a compound as low as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, MCW C2267 Attorney Docket No.
  • the subject may be administered a dose of a compound as high as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg, once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times per week in order to treat the disease or disorder in the subject.
  • a compound as high as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg,
  • Minimal and/or maximal doses of the compounds may include doses falling within dose ranges having as endpoints any of these disclosed doses (e.g., 2.5 mg – 200 mg).
  • a minimal dose level of a compound for achieving therapy in the disclosed methods of treatment may be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng/kg body weight of the subject.
  • a maximal dose level of a compound for achieving therapy in the disclosed methods of treatment may not exceed about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 1900, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 15000, or 20000 ng/kg body weight of the subject.
  • Minimal and/or maximal dose levels of the compounds for achieving therapy in the disclosed methods of treatment may include dose levels falling within ranges having as endpoints any of these disclosed dose levels (e.g., 500 – 2000 ng/kg body weight of the subject).
  • the cancer to be treated is pancreatic cancer, breast cancer, melanoma cancer, non-small cell lung cancer, or a combination thereof.
  • the method further comprises administering to the subject an additional therapeutic agent.
  • the additional therapeutic agent is AZD3965.
  • the compounds as described herein can be combined with ionizing radiation to inhibit tumor cell formation.
  • the subject is a cell or a human.
  • the subject is a human, and the method comprises administering to the subject the effective amount of the compound, or a pharmaceutically acceptable salt thereof, in combination with the CAR-T cell therapy.
  • the subject is a human, and the method comprises pre- treating CAR-T cells with the compound, or a pharmaceutically acceptable salt thereof, and administering an effective amount of the pre-treated CAR-T cells to the subject.
  • analyzing the labeled sample comprises analyzing the profile of the labeled sample.
  • the profile comprises a proteomic profile.
  • Mito10-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito10-NAC is nearly 2,000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito10-NAC also inhibited cancer cell proliferation. Mito10-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation.
  • Example 1 Synthesis of Mitochondria-Targeted N-Acetylcysteine and Analogs Thereof.
  • a generic synthesis of Mito-NAC compounds is shown in Scheme 1. MCW C2267 Attorney Docket No. 650053.01008 - rt., 12h; ii, EtSi-H, TFA, rt., 1h, 83%; iii, HOBt, DIC, bromo-PEG, pyridine, CH2Cl2, rt., 12h; iv, PPh3, CH3CN, reflux, 48 h; v, EtSi-H, TFA, rt., 1h.
  • HPLC-MS indicated that the product was sufficiently pure and could be used without further purification.
  • the crude product was poured into ether.
  • the insoluble salt was purified by flash chromatography (CH 2 Cl 2 /EtOH) and led to the corresponding trityl-Mito- PEG-NAC (0.3 g, 46% yield).
  • HPLC-MS indicated that the product was sufficiently pure and can be used without further purification.
  • FIG. 2A and 2B show the comparative effects of NAC and Mito 10 -NAC on the proliferation of these cells.
  • Mitochondria-targeted triphenylphosphonium (TPP + ) or previously reported drugs inhibit proliferation of cancer cells by 100–500-fold as compared with untargeted parent drugs (FIG. 3B).
  • Mito 10 -NAC inhibited the proliferation of cancer cells 1,500–2,400 fold greater than NAC (FIGS. 2A-2B and FIG. 3A). This is a totally unexpected finding.
  • This magnitude of differential effect induced by TPP + - containing drugs in cancer cells is unique as demonstrated here using Mito-NAC compounds.
  • Mito10-NAC may synergize with NAC.
  • the synergistic effects of Mito 10 -NAC with AZD3965 were compared.
  • AZD3965 is an MCT-1 inhibitor that is undergoing a Phase I/II clinical trial for cancer therapy.
  • MiaPaCa- 2 cells were treated with Mito 10 -NAC and AZD3965 or NAC, independently and together, and cell growth was monitored continuously.
  • FIG. 3A shows the fold difference between the parent compound and the TPP + -modified compound (with 10 carbons in the linker side chain) is dependent on the parent compound, especially its hydrophobicity.
  • FIG. 3A shows the dose response characteristics of NAC and the TPP + -modified analogs in MiaPaCa-2 cells. The difference between NAC and Mito10-NAC is 1,600-fold.
  • Mito-ATO improved the efficacy of PD-1 blockade immunotherapy.
  • Synergistic antitumor effect of OXPHOS inhibitors and MCT-1/4 inhibitors [00179] The antiproliferative effect of Mito 10 -NAC was enhanced in the presence of AZD3965, an inhibitor of MCT-1 transporter. The extent of the combinatorial effect is consistent with our previously published heat map representation for other mitochondria- targeted drugs.
  • AZD3965 has been reported to enhance intracellular acidosis through increased intracellular lactate and decreased extracellular lactate. Relatively higher concentrations of AZD3965 were used to inhibit cancer cells. At these concentrations, AZD3965 exerts deleterious side effects.
  • Mito10-NAC could inhibit complex I by thiolation of mitochondrial cysteine proteome.
  • results obtained from using the methylated analog of Mito10-NAC indicate that the disruption of mitochondrial cysteine proteome is probably not responsible for Mito10-NAC-induced inhibition of mitochondrial respiration.
  • the exact target of Mito10-NAC and other analogs in mitochondria still needs to be determined. [00182] It is possible that Mito-NAC-mediated antiproliferative effects are due to cell cycle arrest.
  • MiaPaCa-2 (Cat# CRL-1420, human pancreatic cancer cells), MDA-MB-231(Cat# HTB-26, human breast cancer cells), and MCF-7 (Cat# HTB-22, human breast cancer cells).
  • the UACC-62 melanoma cell line was purchased from AddexBio (San Diego, CA; Cat# C0020003) where it was regularly authenticated. All cell lines were grown at 37°C in 5% carbon dioxide.
  • MiaPaCa-2 and MDA-MB-231 cells were maintained in DMEM medium (Thermo Fisher Scientific, Cat# 11965) and supplemented with 10% fetal bovine serum.
  • mitochondrial function indices were determined [00193] For mitochondrial complex I activity measurements, the mitochondrial complex I-induced OCR measurements were carried out in permeabilized cells in the presence of complex I substrates pyruvate/malate and complex II inhibitor malonate (10 mM). The IC50 values were determined as previously reported. [00194] Statistical Analysis. Comparisons between the control and treatment groups were made using an unpaired Student’s t-test analysis.
  • Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res. 76, 3904–3915. https:// doi. org/ 10.1158/ 0008- 5472. Can- 15- 2534 (2016). 19. Cheng, G. et al. Targeting lonidamine to mitochondria mitigates lung tumorigenesis and brain metastasis. Nat. Commun. 10, 2205. https:// doi. org/ 10. 1038/ s41467- 019- 10042-1 (2019). 20. Zielonka, J. et al.
  • Mitochondria-targeted triphenylphosphonium-based compounds Syntheses, mechanisms of action, and thera-peutic and diagnostic applications. Chem. Rev.117, 10043–10120. https:// doi. org/ 10.1021/ acs. chemr ev.7b00042 (2017). 21. Murphy, M. P. & Hartley, R. C. Mitochondria as a therapeutic target for common pathologies. Nat. Rev. Drug Discov. 17, 865–886. https:// doi. org/ 10. 1038/ nrd. 2018.174 (2016). 22. Cheng, G. et al. Mitochondria-targeted vitamin E. analogs inhibit breast cancer cell energy metabolism and promote cell death.
  • Clause 7. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is H or C1-C4 alkyl; R 2 is H; and W is NH or O.
  • Clause 8. The compound of clause 7, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-c), (I-d), or (I-e) d), t is 1-20; u is 1-10; and v is 1-10.
  • Clause 9. The compound of clause 1, which is selected from the group consisting of , MCW C2267 Attorney Docket No. 650053.01008 [00206] Clause 10.
  • Clause 11 The compound of clause 1, or a pharmaceutically acceptable salt thereof, which is isotopically labeled.
  • Clause 11. The compound of clause 10, or a pharmaceutically acceptable salt thereof, wherein the compound is 13 C labeled.
  • Clause 12. The compound of clause 11, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (I-f) f).
  • Clause 13. the compound is , wherein n is 1-20.
  • Clause 14 A pharmaceutical composition comprising a compound of any one of clauses 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a method of enhancing CAR-T cell therapy in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of clauses 1-13, or a pharmaceutically acceptable salt thereof.
  • Clause 20 The method of clause 19, wherein the subject is a cell or a human.
  • Clause 21 The method of clause 20, wherein the subject is a human, and wherein the method comprises administering to the subject the effective amount of the compound, or a pharmaceutically acceptable salt thereof, in combination with the CAR-T cell therapy.
  • Clause 22 Clause 22.
  • Clause 23 A method of analyzing a sample, the method comprising: contacting the sample with an isotopically labeled compound of any one of clauses 10-13, or a pharmaceutically acceptable salt thereof, thereby producing a labeled sample, and analyzing the labeled sample.
  • Clause 24 The method of clause 23, wherein the sample comprises a cell.

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Abstract

La présente invention concerne des composés de N-acétylcystéine ciblant les mitochondries et des compositions pharmaceutiques de ceux-ci. Les présents composés peuvent être utiles pour le traitement du cancer et l'amélioration de la thérapie cellulaire CAR-T. Les présents composés peuvent être marqués par voie isotopique, ce qui peut être utile pour le marquage et l'analyse d'un échantillon. Les présents composés peuvent cibler les mitochondries dans des cellules cancéreuses et présentent effet antitumoral amélioré et une toxicité réduite.
EP23875746.2A 2022-10-05 2023-10-04 N-acétylcystéine ciblant les mitochondries et analogues Pending EP4598516A2 (fr)

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