WO2024077062A2 - Mitochondria-targeted n-acetylcysteine and analogs - Google Patents
Mitochondria-targeted n-acetylcysteine and analogs Download PDFInfo
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- WO2024077062A2 WO2024077062A2 PCT/US2023/075944 US2023075944W WO2024077062A2 WO 2024077062 A2 WO2024077062 A2 WO 2024077062A2 US 2023075944 W US2023075944 W US 2023075944W WO 2024077062 A2 WO2024077062 A2 WO 2024077062A2
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- pharmaceutically acceptable
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- 241000894007 species Species 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
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- 229940032147 starch Drugs 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000011044 succinic acid Nutrition 0.000 description 1
- 150000003444 succinic acids Chemical class 0.000 description 1
- 125000000542 sulfonic acid group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical class S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
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- 230000001839 systemic circulation Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical class C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
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- 229940100615 topical ointment Drugs 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 1
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- 229940072651 tylenol Drugs 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 238000012762 unpaired Student’s t-test Methods 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
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- 238000012447 xenograft mouse model Methods 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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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
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
-
- 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
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.
- n 6, 8, 10, 12, 14, or [0061]
- m 1, X is Br, and Y is Cl. and the compound is , wherein n is 1-20.
- n is 6, 8, 10, 12, 14, or 16.
- MCW C2267 Attorney Docket No. 650053.01008 [0062]
- m is 1, X is Br, and Y is CF3.
- the compound has a structure , wherein n is 1-20.
- n is 6, 8, 10, 12, 14, or [0063]
- R 1 is , R 2 is H, W is NH, and L is L1-R A -L2.
- L 1 and L 2 are methylene, and R A is arylene or cycloalkylene.
- the compound is .
- R A is phenylene.
- the compound is .
- n is 3, 4, 5, or 6.
- n is 4.
- L 1 is absent, L 2 MCW C2267 Attorney Docket No. 650053.01008 embodiments, the compound , wherein q is 1-19. For example, q is 3, 4, 5, the compound is .
- 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.
- effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate.
- Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts.
- Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
- sodium bicarbonate component of the effervescent couple may be present.
- 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 demonstrates the effect of mitochondria-targeted thiol compounds, e.g., the compounds of formula (I) as described herein, in cancer cell proliferation.
- Numerous reports have shown in both in vitro and in vivo cancer studies that conjugation of drugs to a triphenylphosphonium (TPP + ) moiety linked through an alkyl side chain can selectively target mitochondria of cancer cells more so than normal cells.
- TPP + triphenylphosphonium
- the more negative mitochondrial membrane potential of cancer cells as compared with control, nontransformed cells is responsible for enhanced uptake and retention of positively charged drugs conjugated to TPP + .
- Enhanced accumulation of TPP + -modified drugs e.g., Mito-vitamin-E
- tumor MCW C2267 Attorney Docket No.
- mitochondria-targeted NAC (Mito10-NAC) was synthesized by attaching an alkyl side chain containing a TPP + moiety (FIG.1A).
- Mito10-NAC has a free sulfhydryl group, so the molecule may exhibit similar antioxidant- and redox-modulating properties.
- Age-related mitochondrial decline was attributed to a breakdown in intracellular amino acid homeostasis, cysteine in particular. Cysteine is most toxic for mitochondria, and elevated non-vacuolar cysteine impairs mitochondrial respiration.
- 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.
- 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 disclosed herein, or a pharmaceutically acceptable salt thereof.
- one compound as disclosed herein may be administered, but in alternate embodiments, multiple compounds as disclosed herein may be administered.
- the term “effective amount” refers to an amount sufficient to achieve a desired result, including prevention or treatment of a disease.
- the term “effective amount” includes a "therapeutically effective amount.”
- therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduction or inhibition of cell growth in the case of cancers.
- 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.
- “Mammals” means any member of the class Mammalia including, but not limited to, humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like.
- the term "subject” does not denote a particular age or sex.
- the subject is a human, particularly a human having cancer.
- 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.
- 650053.01008 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.
- 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 compounds as described herein can be combined with immune therapies to inhibit tumor cell formation.
- Suitable immune therapies can include, but are not limited to, immune checkpoint blockade therapy, cellular therapy, and other MCW C2267 Attorney Docket No. 650053.01008 immune therapies known in the art.
- Immune checkpoint blockade therapy may involve blocking immune checkpoint proteins produced by immune system cells, such as T cells, from binding with partner proteins on other cells, such as tumor cells.
- viable cells may be injected, grafted, or implanted into a patient to replace or repair damaged tissue and/or cells.
- the compounds as disclosed herein can, when combined with conventional treatment protocols, increase the effectiveness of conventional cancer treatments.
- CAR-T cell refers to a chimeric antigen receptor-expressing T-cell.
- CARs chimeric antigen receptors
- scFvs single-chain variable fragments
- CARs can directly recognize cell surface antigens, independent of MHC-mediated presentation, permitting the use of a single receptor construct specific for any given antigen in all patients.
- CAR-T cell therapy can be a therapeutic approach for, for example, the treatment of cancer-related (e.g., B and T cell lymphomas) and immune-related malignancies.
- CAR-T T cells can comprise patient-derived memory CDS+ T cells modified to express a recombinant T cell receptor specific for a known antigen present on, for example, a tumor of interest. While the present disclosure is generally described in the context of using CAR-T cell therapy for the treatment of cancer, it is to be understood that such therapy also finds utility in the treatment of other indications.
- 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.
- the method comprises contacting the sample with an isotopically labeled compound as described herein, or a pharmaceutically acceptable salt thereof, thereby producing a labeled sample, and analyzing the labeled sample.
- the sample comprises a cell.
- analyzing the labeled sample in the method comprises analyzing a profile or an image of the labeled sample.
- profile includes a nucleic acid profile or proteomic profile.
- the nucleic acid profile or proteomic profile is an analysis of characteristics including but not limited to genetic constitution, gene expression, and protein modification.
- analyzing the labeled sample comprises analyzing the profile of the labeled sample.
- the profile comprises a proteomic profile.
- proteomic profile is used to refer to a representation of the expression pattern of a plurality of proteins in a biological sample, e.g., a biological fluid at a given time.
- the proteomic profile can, for example, be represented as a mass spectrum, but other representations based on any physicochemical or biochemical properties of the proteins are also included.
- the method comprises analyzing the proteomic profile of the labeled sample using mass spectrometry.
- analyzing the labeled sample comprises analyzing the image of the labeled sample.
- the method comprises generating the image of the labeled sample using magnetic resonance imaging (MRI).
- MRI magnetic resonance imaging
- Kits Another aspect of the disclosure provides a kit comprising a pharmaceutical composition comprising the compounds as disclosed herein and instructional material.
- MCW C2267 Attorney Docket No. 650053.01008
- the term "instructional material" refers to a publication, a recording, a diagram, or any other medium of expression which is used to communicate the usefulness of the present pharmaceutical composition for one of the purposes set forth herein in a human.
- the instructional material can also, for example, describe an appropriate dose of the present pharmaceutical composition.
- the instructional material of the present kit can, for example, be affixed to a container which contains a pharmaceutical composition as disclosed herein or be shipped together with a container which contains the pharmaceutical composition.
- the instructional material can be shipped separately from the container with the intention that the instructional material and the pharmaceutical composition be used cooperatively by the recipient.
- EXAMPLES [00135] The following examples are, of course, offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and the following examples and fall within the scope of the appended claims. [00136] In the following examples, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito 10 -NAC) that is functionally similar to NAC was synthesized and studied.
- Mito 10 -NAC triphenylphosphonium group
- 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.
- Mito10-NAC was prepared in two steps, by activating the carboxylic acid using N,N′-diisopropylcarbodiimide (DIC)/hydroxybenzotriazole (HOBt) followed by the addition of (10-aminodecyl)-triphenylphosphonium bromide in the presence of triethylamine in dichloromethane (CH 2 Cl 2 ). Deprotection of thiol by 2,2,2-trifluoroacetic acid (TFA) and triethylsilane delivered the Mito10-NAC. The synthesis of Mito10-NAC is shown in Scheme 3. MCW C2267 Attorney Docket No.
- 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.
- TPP + modification will likely induce a greater fold difference in antiproliferative effect and inhibition of mitochondrial respiration in tumor cells due to the more negative mitochondrial membrane potential of tumor cells as compared with normal cells. It has previously been shown that TPP + incorporation to the mitochondria- targeted drug is essential for its mitochondrial accumulation and antiproliferative efficacy in cancer cells.
- CAR T cell therapy involves reprogramming a patient’s own T cells to recognize and attack a specific protein in cancer cells, and then infusing the T cells back into the patient. Often, enhanced oxidant-induced modifications in CAR T cells decrease this ability.
- NAC has been shown to improve the efficacy of adoptive T cell immunotherapy to treat melanoma. In a recent study, the NAC T cells were cultured before they were infused as immunotherapy in a preclinical model of melanoma; this resulted in an improved outcome. T cells treated with NAC were 33-fold more effective than those cultured without NAC. NAC improves the anti-tumor function of exhausted T cells, thereby enhancing therapeutic outcomes for adoptive cell transfer (ACT) therapy.
- ACT adoptive cell transfer
- NAC activates PI3K/Akt, inhibiting Foxo1, and inhibits reactive oxygen species, thereby enhancing the antitumor functionality of T cells.
- the NAC mediated opposing effect on T cells was dependent on the concentration. At low concentrations, NAC had an immunostimulatory effect, and at higher concentrations NAC had a suppressive effect.
- a Phase I clinical trial of NAC, which aims to optimize the metabolic tumor microenvironment, is ongoing. Although the bioavailability of NAC is low, it is MCW C2267 Attorney Docket No. 650053.01008 membrane-permeable and has been shown to cross the blood–brain barrier in humans and rodents.
- Mito10-NAC is considerably more effective in tumor cells, the possibility of enhancing CAR-T cell therapy using Mito10-NAC may be explored. Published reports and an ongoing clinical trial using NAC attest to this possibility.
- Mitochondria-targeted drugs such as Mito-ATO reprogram the tumor microenvironment, inhibiting tumor-suppressive immune cells and activating T cells.
- Mito10-ATO could reverse immunosuppression by regulatory T cells by stimulating the function of effector T cells.
- Mito-ATO induced potent T cell immune responses in local and distant tumor sites, and it decreased myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment.
- Mito-ATO also increased tumor infiltrating CD4+ T cells.
- 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.
- the combination therapy with mitochondria-targeted drugs is a promising option as it could significantly lower the concentration of AZD3965 used in cancer therapy.
- Other mitochondria-targeted drugs i.e., metformin and phenformin
- Mito10-NAC was used at low micromolar levels in combination with AZD3965 to achieve a synergistic inhibition in proliferation.
- the hyperpolarized [1-13C] NAC probe of the hyperpolarized 13C-MRI showed global distribution of NAC, including to the brain. This finding is consistent with previous studies that used isotopically substituted NAC56.
- 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.
- mitochondria-targeted drugs e.g., Mito-magnolol
- AKT phospholipase
- Foxo1 phospholipase
- induced cell cycle arrest in the G1 phase of the cell cycle.
- Future studies investigating the effect of NAC, Mito-NAC, and their methylated analogs on AKT signaling and cell cycle arrest in cancer cells should enhance our understanding of these redox-sensitive thiols. [00183] All the experiments were performed in different cancer cell lines. Based on the previous publications in which mitochondrial OXPHOS inhibitors were translated to in vivo mouse xenograft models, Mito10-NAC and analogs may show similar potency in mouse xenografts as well.
- NACA N-acetylcysteine amide
- NAC a more lipophilic, membrane-permeable and bloodbrain barrier permeant analog of the antioxidant thiol, NAC
- NACA was shown to be more potent than NAC in reversing paracetamol toxicity and oxidative stress-induced diseases (see Example 2).
- NACA was shown to enhance the therapeutic effect of neural stem cell-based antiglioma oncolytic virotherapy.
- 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.
- MCF-7 cells were maintained in MEM- ⁇ (Thermo Fisher Scientific, Cat# 12571) containing 10% fetal bovine serum.
- UACC- 62 cells were maintained in RPMI 1640 medium (Thermo Fisher Scientific, Cat# 11875) and supplemented with 10% fetal bovine serum. All cells were stored in liquid nitrogen and used within 20 passages after thawing.
- Cell proliferation measurements The IncyCyte Live-Cell Analysis System was used to monitor cell proliferation. This imaging system is noninvasive and enables continuous monitoring of cell confluence over several days. In a 96-well plate, cells were plated at 1,000 cells per well in triplicates and left to adhere overnight.
- Mitochondrial Respiration Measurements Mitochondrial oxygen consumption was measured in the Seahorse XF-96 Extracelluar Flux Analyzer (Agilent, North Billerica, MA). The bioenergetic function assay was used to determine the intact cell mitochondrial function of cells in response to drug treatment. After cells were treated with NAC or Mito 10 - NAC for 24 h, eight baseline OCR measurements were taken before injection of oligomycin (1 MCW C2267 Attorney Docket No.
- 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.
- Mitochondria-targeted hydroxyurea inhibits OXPHOS and induces antiproliferative and immunomodulatory effects. iScience 24, 102673. https:// doi. org/ 10.1016/j. isci.2021.102673 (2021). 37. Crunkhorn, S. Targeting the mitochondria to block tumour growth. Nat. Rev. Drug Discov.20, 97. https:// doi. org/ 10.1038/ d41573-021-00001-1 (2021). 38. Zorova, L. D. et al. Mitochondrial membrane potential. Anal. Biochem. 552, 50–59. https:// doi. org/ 10.1016/j. ab.2017.07.009 (2016). 39. Dong, L.
- a compound of formula (I), or a pharmaceutically acceptable salt thereof wherein R 1 is H, C 1 -C 4 ; R 2 is H or C1-C4 W is NH, O, or S, L is C 1 -C 20 alkylene, C 2 -C 20 alkenylene, L 1 -R A -L 2 , or amino acid; L1 and L2 are each independently absent or C1-C10 alkylene; R A is –(CH 2 CH 2 O) q –, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently CF3, Me, Cl, OMe, C(O)CH3, NO2, 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-mercapto-N-eth
- 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 treating cancer 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.
- MCW C2267 Attorney Docket No. 650053.01008
- Clause 16 The method of clause 15, wherein the cancer is pancreatic cancer, breast cancer, melanoma cancer, non-small cell lung cancer, or a combination thereof.
- Clause 17. The method of any one of clauses 15-16, further comprising administering to the subject an additional therapeutic agent.
- Clause 18 The method of clause 17, wherein the additional therapeutic agent is AZD3965.
- 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.
- analyzing the labeled sample comprises analyzing a profile or an image of the labeled sample.
- Clause 26 The method of clause 25, wherein analyzing the labeled sample comprises analyzing the profile of the labeled sample.
- the profile comprises a proteomic profile.
- Clause 28 The method of clause 27, comprising analyzing the proteomic profile of the labeled sample using mass spectrometry.
- Clause 29 The method of clause 25, wherein analyzing the labeled sample comprises analyzing the image of the labeled sample.
- MCW C2267 Attorney Docket No. 650053.01008
- Clause 30 The method of clause 23, comprising generating the image of the labeled sample using magnetic resonance imaging (MRI).
- MRI magnetic resonance imaging
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Abstract
The present disclosure provides mitochondria-targeted N-acetylcysteine compounds and pharmaceutical compositions thereof. The present compounds may be useful for treating cancer and enhancing CAR-T cell therapy. The present compounds may be isotopically labeled, which may be useful for labeling and analyzing a sample. The present compounds may target mitochondria in carcer cells and have improved anti-tumor effect and reduced toxicity.
Description
MCW C2267 Attorney Docket No. 650053.01008 MITOCHONDRIA-TARGETED N-ACETYLCYSTEINE AND ANALOGS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application claims priority to U.S. Provisional Patent Application No. 63/413,461, filed October 5, 2022, the content of which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] Not Applicable. BACKGROUND [0003] 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. However, NAC is not readily bioavailable and is used in high concentrations. [0004] There remains a need for compounds that have improved properties, including increased potency and reduced cell toxicity, that are effective in inhibiting cancer cell proliferation. SUMMARY OF THE INVENTION [0005] Disclosed herein are modified N-acetylcysteine (NAC) compounds, pharmaceutical compositions comprising the compounds, kits, and methods of use thereof. [0006] In one aspect, 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-RA-L2, or amino acid; L1 and L2 are each independently absent or C1-C10 alkylene; RA is –(CH2CH2O)q–, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently CF3, Me, Cl, OMe, C(O)CH3, NO2, 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-mercapto-N-ethylpropanamide. [0007] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is isotopically labeled. For example, the compound can be 13C labeled. [0008] In another aspect, 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. [0009] In a further aspect, 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. [0010] In another aspect, 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. [0011] In another aspect, the present disclosure provides a method of analyzing a sample. The method comprises contacting the sample with an isotopically labeled compound (e.g., a 13C labeled compound) as described herein, or a pharmaceutically acceptable salt thereof, thereby producing a labeled sample, and analyzing the labeled sample. [0012] In yet another aspect, the disclosure provides a kit. The kit comprises the pharmaceutical composition as described herein and an instructional material. BRIEF DESCRIPTION OF THE DRAWINGS [0013] FIG.1A demonstrates structures of NAC and Mito10-NAC analogs. [0014] FIG. 1B demonstrates calculated partition coefficients and relative hydrophobic regions in NAC and Mito10-NAC analogs. [0015] FIGS. 2A-2B show effects of NAC and Mito10-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. 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, n = 4. [0016] 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. 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. The folder of differences as indicated were calculated by the potency difference of the IC50 values between each mitochondria-targeted drug and its parental compound. 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. [0017] FIGS. 4A-4B show effects of Mito10-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 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, n = 4. [0018] 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. FIG. 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 (IC50 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. The corresponding representative fluorescence images are shown in the left (24 h) and right (48 h) panels. Data shown are the mean ± SD, n = 4. [0019] FIGS. 6A-6B demonstrate effects of NAC and Mito10-NAC on mitochondria oxygen consumption in either intact cells or by mitochondrial complex I in human pancreatic cancer (MiaPaCa-2) cells. FIG.6A shows effects of NAC and Mito10-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. After eight baseline OCR measurements, the response to mitochondrial modulators (oligo, DNP, and rotenone/antimycin A, as described in the Methods section) were recorded. *p < 0.05, **p < 0.01 versus control at the last baseline measurements. Data shown are the mean ± SD, n = 4. FIG.6B demonstrates effects of NAC and Mito10-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. The mitochondria basal OCR (A, bottom), or mitochondrial complex I dependent OCR direct treatment (B, bottom) were plotted against the concentrations of treatments. Dashed lines represent the fitting curves used to determine the IC50 values as indicated. Data shown are the mean±SD, n = 4. [0020] 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. Data shown are the mean ± SD (n=5). Representative cell images are shown as a segmentation mask illustrated in brown when control cells reached ~90% confluence (vertical ## dashed line). ** p<0.01 vs control. p<0.01 vs single compound alone. (FIGS. 7E and 7F) Cell confluence (control cells reached ~90% confluence) is plotted against concentration for the synergistic calculation. Panel B shows the combination index-fraction affected plots.
MCW C2267 Attorney Docket No. 650053.01008 Fraction affected parameter is used as a measure of the drug’s efficiency, with a value of 0 indicating complete inhibition of cell confluence and a value of 1 indicating the lack of effect on cell confluence. Mito-NAC concentration range used to calculate confidence interval are 2, 4, 6, 8, 10, 12.5, 15, 25, and 50 µM. Data shown are the means ± SD, n = 4. [0021] 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 Mito10-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. [0022] 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. Representative cell images were shown as segmentation mask illustrated in brown when control cells reached 90% confluence (vertical solid black line). No significant different between two scheduled treatment at the same concentration. Data shown are the mean±SD, n=4. DETAILED DESCRIPTION OF THE INVENTION [0023] Before the present materials and methods are described, it is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims. [0024] As used in this specification and the claims, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise. For example, the term “a compound” should be interpreted to mean “one or more compounds” unless the context clearly dictates otherwise. As used herein, 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. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean up to plus or minus 10% of the particular term and “substantially” and “significantly” will mean more than plus or minus 10% of the particular term. [0026] As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter. [0027] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March 's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. [0028] The term "alkyl" as used herein, means a straight or branched chain saturated hydrocarbon. The alkyl can be a С1-4alkyl. Representative examples of 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. [0029] The term "alkylene," as used herein, means a divalent group derived from a straight or branched chain saturated hydrocarbon. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, and CH2CH(CH3)CH(CH3)CH2-. [0030] The term "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. [0031] The term “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. [0032] The term “aryl,” as used herein, means a carbocyclic aromatic group (e.g., phenyl or a bicyclic aryl). The term "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. For example, a bicyclic aryl can be a phenyl fused to a cycloalkyl moiety. Examples of aryl include naphthyl, dihydronaphthalenyl, tetrahydronaphthalenes, indanyl, or indenyl. The aryl (e.g., phenyl and bicyclic aryls) is attached to the parent molecular moiety through any carbon atom contained within the aryl. [0033] The term “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. Examples of 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). [0034] The term "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. Examples of 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. [0035] The term “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 C3-10 rings,
. term "halogen" or “halo” means a chlorine, bromine, iodine, or fluorine atom.
[0037] Terms such as "alkyl," "cycloalkyl," "alkylene," “arylene,” or "cycloalkylene," etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., "С1-С4alkyl," "C1-4alkyl," "C3-6cycloalkyl," "C1-4alkylene"). These designations are used as generally understood by those skilled in the art. For example, the representation "C" followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, "C3alkyl" is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as in "C1-C4" or "C1-4," the members of the group that follows may have any number of carbon atoms falling within the recited range. A "C1-C4alkyl" or "C1-4alkyl," for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched). [0038] If 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). [0039] Unless otherwise stated, 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. Unless otherwise stated, all tautomeric and regioisomeric forms of the compounds of the invention are within the scope of the invention. [0040] The term "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.
MCW C2267 Attorney Docket No. 650053.01008 For use in medicine, the 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. [0041] 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. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids. Specific examples of 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, cyclohexylaminosulfonate, P-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate. [0042] Furthermore, where the compounds of the invention carry an acidic moiety, 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. In another embodiment, 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. [0043] 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 (C1-C6) halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e.,
MCW C2267 Attorney Docket No. 650053.01008 dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others. [0044] The term "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. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. 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., 3H, and carbon-14, i.e., 14C, 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., 2H, 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 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. 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. [0045] 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). The concentration of such isotopes, e.g., deuterium, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor” as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. For example, if 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. 650053.01008 incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). [0046] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications and patents specifically mentioned herein are incorporated by reference for all purposes including describing and disclosing the chemicals, cell lines, vectors, animals, instruments, statistical analysis and methodologies which are reported in the publications which might be used in connection with the invention. All references cited in this specification are to be taken as indicative of the level of skill in the art. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. [0047] The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. In various embodiments, the present disclosure provides mitochondria-targeted NAC analogs and uses thereof. [0048] Compounds [0049] In one aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein
;
MCW C2267 Attorney Docket No. 650053.01008 R2 is H or C1-C4 alkyl; W is NH, O, or S, L is C1-C20 alkylene, C2-C20 alkenylene, L1-RA-L2, or amino acid; L1 and L2 are each independently absent or C1-C10 alkylene; RA is –(CH2CH2O)q–, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently CF3, Me, Cl, OMe, C(O)CH3, NO2, 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-mercapto-N-ethylpropanamide. [0050] In some embodiments, X is F, Cl, Br, or I. In some embodiments, X is Br. In some embodiments, X is 2,2,2-trifluoroacetate or acetate. [0051] In some In some embodiments, R1 is H or C1-C4 alkyl.
[0052] In some embodiments, R2 is H. In some embodiments, W is NH or O. In some embodiments, R2 is H and W is NH or O. [0053] In some embodiments, L is C1-C20 alkylene. In some embodiments, L is L1-RA-L2. In some embodiments, L is L1-RA-L2 and RA is –(CH2CH2O)q–. In some embodiments, L is L1- RA-L2 and RA is arylene. In some embodiments, L is L1-RA-L2 and RA is cycloalkylene. [0054] In some embodiments, m is 0 or 1. In some embodiments, Y at each occurrence is independently CF3, Me, Cl, or OMe. In some embodiments, m is 1 and Y at each occurrence is independently CF3, Me, Cl, OMe. [0055] In some embodiments, R2 is methyl. In some embodiments, R1 is and R2 is methyl. In some embodiments, R1 is , R2 is methyl, W is NH, and L is C1-C20
MCW C2267 Attorney Docket No. 650053.01008 alkylene. In some embodiments, the , wherein n is 1-20. In some such embodiments, n is 6, 8, 10, n is 10 and
the compound . [0056] In of formula (I), or a pharmaceutically acceptable
salt thereof, a structure a) wherein n is 1-20.
[0057] In some embodiments, 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. In some embodiments, m is 1, X is Br, and Y at each occurrence is independently Me, OMe, Cl, or CF3. [0058] In some embodiments, the , wherein n is 1-20. For example, n is 6, 8, 10, 12, 14, or 16. In
is 10 and the compound . In some such embodiments, n is 12 and the compound is
MCW C2267 Attorney Docket No. 650053.01008 is the
compound , wherein n is 1-20. For example, n is 6, 8, 10, 12, 14, or 16.
[0060] In some embodiments, m is 1, X is Br, and Y is OMe. In some embodiments, the , wherein n is 1-20. For example, n is 6, 8, 10, 12, 14, or
[0061] In some embodiments, m is 1, X is Br, and Y is Cl. and the compound is , wherein n is 1-20. For example, n is 6, 8, 10, 12, 14, or 16.
MCW C2267 Attorney Docket No. 650053.01008 [0062] In some embodiments, m is 1, X is Br, and Y is CF3. In some embodiment, the compound has a structure , wherein n is 1-20. For example, n is 6, 8, 10, 12, 14, or
[0063] In some embodiments, R1 is , R2 is H, W is NH, and L is L1-RA-L2. For example, L1 and L2 are methylene, and RA is arylene or cycloalkylene. In some embodiments, the compound is . As an example, RA is phenylene. As a non-
limiting example, the compound is . [0064] In some embodiments, the
of formula (I-b) b)
wherein n is 1-10. For example, n is 3, 4, 5, or 6. In some embodiments, n is 4. [0065] In some example, L1 is absent, L2
MCW C2267 Attorney Docket No. 650053.01008 embodiments, the compound , wherein q is 1-19. For example, q is 3, 4, 5, the compound is
.
H or C1-C4 alkyl, R2 is H, and W is NH or O. [0067] In some embodiments, R1 is H or C1-C4 alkyl, R2 is H, W is NH or O, and the compound has a structure of formula (I-c), (I-d), or (I-e) d), wherein t
[0068] In some embodiments, R1 is methyl in the compound of formula (I-c), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is t
MCW C2267 Attorney Docket No. 650053.01008 [0069] In some embodiments, R1 is methyl in the compound of formula (I-d), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is . For example, u is 3, 4, 5, or 6. R1 is methyl in the compound of formula (I-e), or a
salt thereof. In some embodiments, the compound is . For example, 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] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is isotopically labeled. [0073] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is 13C labeled. For example, the carbon atom of a carbonyl group (C=O) of the present compound may be labeled with 13C. [0074] In some embodiments, the 13C labeled compound of formula (I), or a pharmaceutically acceptable salt thereof, has a structure of formula (I-f) f). [0075] In some
, wherein n is 1-20. For example, n is 6, 8, 10, 12, 14, or 16.
as described herein may have an isotopic enrichment factor for each designated 13C atom of at least 5, at least 10, at least 20, at least 50, or at least 90. [0077] 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. [0079] The pharmaceutical composition may include the compound in a range of about 0.1 to 2000 mg. In some embodiments, 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. 650053.01008 about 1, 2, 3, 4, 5, or 6 hours post-administration), the concentration of the compound at the site of action may be within a concentration range bounded by end-points selected from 0.001 µM, 0.005 µM, 0.01 µM, 0.5 µM, 0.1 µM, 1.0 µM, 10 µM, and 100 µM (e.g., 0.1 µM - 1.0 µM). [0080] The compounds may be formulated as a pharmaceutical composition that includes a carrier. For example, the carrier may be selected from the group consisting of proteins, carbohydrates, sugar, talc, magnesium stearate, cellulose, calcium carbonate, and starch-gelatin paste. [0081] 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; examples of 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 SMCC™). Suitable lubricants, including agents that act on the flowability of the powder to be compressed, may include colloidal silicon dioxide, such as Aerosil®200, talc, stearic acid, magnesium stearate, calcium stearate, and silica gel. Examples of sweeteners may include any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, and acsulfame. Examples of flavoring agents are Magnasweet® (trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like. Examples of 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. [0082] Suitable diluents may include pharmaceutically acceptable inert fillers, such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and mixtures of any of the foregoing. Examples of 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. [0083] 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.
MCW C2267 Attorney Docket No. 650053.01008 [0084] Examples of effervescent agents are effervescent couples such as an organic acid and a carbonate or bicarbonate. Suitable organic acids include, for example, citric, tartaric, malic, fumaric, adipic, succinic, and alginic acids and anhydrides and acid salts. Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate. Alternatively, only the sodium bicarbonate component of the effervescent couple may be present. [0085] Pharmaceutical 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). [0086] Pharmaceutical 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. [0087] 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. For example, the active ingredient may be delivered from the patch by iontophoresis. [0088] Pharmaceutical 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. [0089] For applications to the eye or other external tissues, for example the mouth and skin, the pharmaceutical compositions are in some embodiments applied as a topical ointment or cream. When formulated in an ointment, the compound may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, 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. [0090] Pharmaceutical compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
MCW C2267 Attorney Docket No. 650053.01008 [0091] Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or enemas. [0092] Pharmaceutical 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. [0093] 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. [0094] Pharmaceutical compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. [0095] 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. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. [0096] 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. [0097] Optionally, 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. In some embodiments of the disclosed methods, 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. In some embodiments, 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. [0098] Methods of Use [0099] N-acetylcysteine (NAC) was first approved by the US Food and Drug Administration in 1963 as a drug to treat excessive mucous production in respiratory diseases including cystic fibrosis. It was later used as treatment for paracetamol (i.e., acetaminophen or Tylenol) poisoning. 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. [00100] The present disclosure demonstrates the effect of mitochondria-targeted thiol compounds, e.g., the compounds of formula (I) as described herein, in cancer cell proliferation. Numerous reports have shown in both in vitro and in vivo cancer studies that conjugation of drugs to a triphenylphosphonium (TPP+) moiety linked through an alkyl side chain can selectively target mitochondria of cancer cells more so than normal cells. The more negative mitochondrial membrane potential of cancer cells as compared with control, nontransformed cells is responsible for enhanced uptake and retention of positively charged drugs conjugated to TPP+. Enhanced accumulation of TPP+-modified drugs (e.g., Mito-vitamin-E) in tumor
MCW C2267 Attorney Docket No. 650053.01008 tissues was observed in mice xenograft administered with the drug. In the present disclosure, mitochondria-targeted NAC (Mito10-NAC) was synthesized by attaching an alkyl side chain containing a TPP+ moiety (FIG.1A). Mito10-NAC has a free sulfhydryl group, so the molecule may exhibit similar antioxidant- and redox-modulating properties. Age-related mitochondrial decline was attributed to a breakdown in intracellular amino acid homeostasis, cysteine in particular. Cysteine is most toxic for mitochondria, and elevated non-vacuolar cysteine impairs mitochondrial respiration. [00101] Further, the present disclosure compared the relative antiproliferative potencies of NAC, Mito10-NAC, and their methylated analogs in several cancer cells. In representative studies, the present disclosure showed that Mito10-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 IC50 for Mito10-MeNAC is 1.9 µM compared with 9.6 µM for Mito10-NAC), indicating that the antiproliferative effect is not related to the antioxidant or radical scavenging mechanism. Thus, the present disclosure demonstrates the antiproliferative effects of the mitochondria-targeted compounds as described herein in cancer cells. [00102] Method of Treating Cancer [00103] In another aspect, 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 disclosed herein, or a pharmaceutically acceptable salt thereof. In one embodiment, one compound as disclosed herein may be administered, but in alternate embodiments, multiple compounds as disclosed herein may be administered. [00104] As used herein, the term “effective amount” refers to an amount sufficient to achieve a desired result, including prevention or treatment of a disease. The term “effective amount” includes a "therapeutically effective amount." The term "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduction or inhibition of cell growth in the case of cancers. 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 [00105] As used herein, the term "tumor" or "cancer" refers to any abnormal proliferation of tissues, including solid and non-solid tumors. For instance, the 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. [00106] As used herein, the term "subject" refers mammals, non-mammals, and/or cells. "Mammals" means any member of the class Mammalia including, but not limited to, humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. The term "subject" does not denote a particular age or sex. Preferably, the subject is a human, particularly a human having cancer. [00107] As used herein, 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. [00108] As used herein, the term "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. [00109] 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. [00110] In some embodiments of the disclosed treatment methods, 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. 650053.01008 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. In some embodiments, 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. 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). [00111] In some embodiments, 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. In some embodiments, 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). [00112] In some embodiments, the cancer to be treated is pancreatic cancer, breast cancer, melanoma cancer, non-small cell lung cancer, or a combination thereof. [00113] In some embodiments, the method further comprises administering to the subject an additional therapeutic agent. In some embodiments, the additional therapeutic agent is AZD3965. [00114] In some embodiments, the compounds as described herein can be combined with ionizing radiation to inhibit tumor cell formation. [00115] In some embodiments, the compounds as described herein can be combined with immune therapies to inhibit tumor cell formation. Suitable immune therapies can include, but are not limited to, immune checkpoint blockade therapy, cellular therapy, and other
MCW C2267 Attorney Docket No. 650053.01008 immune therapies known in the art. Immune checkpoint blockade therapy may involve blocking immune checkpoint proteins produced by immune system cells, such as T cells, from binding with partner proteins on other cells, such as tumor cells. In cellular therapy, viable cells may be injected, grafted, or implanted into a patient to replace or repair damaged tissue and/or cells. [00116] In some embodiments, the compounds as disclosed herein can, when combined with conventional treatment protocols, increase the effectiveness of conventional cancer treatments. [00117] Method of Enhancing CAR-T Cell Therapy [00118] In another aspect, the present disclosure provides a method of enhancing CAR- T cell therapy in a subject in need thereof. The method comprises administering to the subject an effective amount of the compound as disclosed herein, or a pharmaceutically acceptable salt thereof. [00119] “CAR-T cell” refers to a chimeric antigen receptor-expressing T-cell. A skilled artisan would appreciate that chimeric antigen receptors (CARs) are a type of antigen-targeted receptor composed of intracellular T-cell signaling domains fused to extracellular tumor- binding moieties, most commonly single-chain variable fragments (scFvs) from monoclonal antibodies. CARs can directly recognize cell surface antigens, independent of MHC-mediated presentation, permitting the use of a single receptor construct specific for any given antigen in all patients. “CAR-T cell therapy” can be a therapeutic approach for, for example, the treatment of cancer-related (e.g., B and T cell lymphomas) and immune-related malignancies. CAR-T T cells can comprise patient-derived memory CDS+ T cells modified to express a recombinant T cell receptor specific for a known antigen present on, for example, a tumor of interest. While the present disclosure is generally described in the context of using CAR-T cell therapy for the treatment of cancer, it is to be understood that such therapy also finds utility in the treatment of other indications. [00120] In some embodiments, the subject is a cell or a human. [00121] In some embodiments, 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. [00122] In some embodiments, 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. [00123] Method of Analyzing a Sample
MCW C2267 Attorney Docket No. 650053.01008 [00124] Another aspect of the disclosure provides a method of analyzing a sample. The method comprises contacting the sample with an isotopically labeled compound as described herein, or a pharmaceutically acceptable salt thereof, thereby producing a labeled sample, and analyzing the labeled sample. [00125] In some embodiments, the sample comprises a cell. [00126] In some embodiments, analyzing the labeled sample in the method comprises analyzing a profile or an image of the labeled sample. The term "profile" as used herein includes a nucleic acid profile or proteomic profile. The nucleic acid profile or proteomic profile is an analysis of characteristics including but not limited to genetic constitution, gene expression, and protein modification. Nucleic acid profiles using cDNA, and proteomic profiles, analyze genetic constitution or gene expression (i.e., gene products that are RNA and protein), respectively. The "image" of a sample may be obtained by any of a variety of advanced microscopy and imaging techniques known to those of skill in the art. Examples include, but are not limited to, bright-field microscopy, dark-field microscopy, phase contrast microscopy, differen-tial interference contrast microscopy (DIC), and the like, where the combination of magnification and contrast mechanism provides images having cellular or sub-cellular image resolution. [00127] In some embodiments, analyzing the labeled sample comprises analyzing the profile of the labeled sample. [00128] In some embodiments, the profile comprises a proteomic profile. The term "proteomic profile" is used to refer to a representation of the expression pattern of a plurality of proteins in a biological sample, e.g., a biological fluid at a given time. The proteomic profile can, for example, be represented as a mass spectrum, but other representations based on any physicochemical or biochemical properties of the proteins are also included. [00129] In some embodiments, the method comprises analyzing the proteomic profile of the labeled sample using mass spectrometry. [00130] In some embodiments, analyzing the labeled sample comprises analyzing the image of the labeled sample. [00131] In some embodiments, the method comprises generating the image of the labeled sample using magnetic resonance imaging (MRI). [00132] Kits [00133] Another aspect of the disclosure provides a kit comprising a pharmaceutical composition comprising the compounds as disclosed herein and instructional material.
MCW C2267 Attorney Docket No. 650053.01008 [00134] The term "instructional material" refers to a publication, a recording, a diagram, or any other medium of expression which is used to communicate the usefulness of the present pharmaceutical composition for one of the purposes set forth herein in a human. The instructional material can also, for example, describe an appropriate dose of the present pharmaceutical composition. The instructional material of the present kit can, for example, be affixed to a container which contains a pharmaceutical composition as disclosed herein or be shipped together with a container which contains the pharmaceutical composition. Alternatively, the instructional material can be shipped separately from the container with the intention that the instructional material and the pharmaceutical composition be used cooperatively by the recipient. EXAMPLES [00135] The following examples are, of course, offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and the following examples and fall within the scope of the appended claims. [00136] In the following examples, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito10-NAC) that is functionally similar to NAC was synthesized and studied. 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. These results suggest that the antiproliferative effects of NAC and Mito10-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group- dependent redox modulatory effects. [00137] Example 1. Synthesis of Mitochondria-Targeted N-Acetylcysteine and Analogs Thereof. [00138] 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. [00139] A generic synthesis of 13C labeled Mito-NAC compounds is shown in Scheme 2.
CH2Cl2, rt., 12h; ii, HOBt, DIC, (10-aminodecyl)-triphenylphosphonium bromide hydrochloride, pyridine, CH2Cl2, rt., 12h; ii, EtSi-H, TFA, rt., 1h. [00140] Synthesis of Mito10-NAC [00141] Mito10-NAC was prepared in two steps, by activating the carboxylic acid using N,N′-diisopropylcarbodiimide (DIC)/hydroxybenzotriazole (HOBt) followed by the addition of (10-aminodecyl)-triphenylphosphonium bromide in the presence of triethylamine in dichloromethane (CH2Cl2). Deprotection of thiol by 2,2,2-trifluoroacetic acid (TFA) and triethylsilane delivered the Mito10-NAC. The synthesis of Mito10-NAC is shown in Scheme 3.
MCW C2267 Attorney Docket No. 650053.01008 (10-
- 12 h, 71%; ii, EtSi-H, TFA, rt., 1 h, 83%. [00142] A stirred solution of N-acetyl-S-trityl-L-cysteine (0.3 g, 0.74 mmol) in CH2Cl2/N,N-dimethylformamide (DMF) (15 mL/100 mL) was cooled to 0°C and successively treated with HOBt (0.2 g, 1.48 mmol) and DIC (0.19 g, 1.50 mmol). After stirring for 2 h at room temperature, (10-aminodecyl)-triphenylphosphonium bromide hydrochloride (0.35 g, 0.65 mmol) and triethylamine (188 µL, 0.13 mmol) were added to the mixture. The reaction mixture was stirred overnight at room temperature. Then, CH2Cl2 was added to the mixture as well as water (H2O) (25 mL). The organic layer was dried over sodium sulfate (Na2SO4). The solvent was removed under reduced pressure. The crude product was poured in 100 mL of ether and centrifuged. The insoluble salt was collected and purified by flash chromatography (CH2Cl2/ethanol [EtOH] 9/1) and led to the corresponding trityl-Mito10-NAC (0.41 g, 71% yield). High-performance liquid chromatography–mass spectrometry (HPLC-MS) indicated that the product was sufficiently pure and could be used without further purification. Electrospray ionization–mass spectrometry (ESI-MS) for trityl-Mito10-NAC C52H58N2O2PS+ [M]+, 806.1. [00143] A mixture of trityl-Mito10-NAC (0.25 g, 0.31 mmol), triethylsilane (100 ^L, 0.60 mmol), in trifluoroacetic acid (1 mL) was stirred at room temperature for 1 h. Then, the mixture was purified directly by reverse phase chromatography on C18 column (H2O/acetonitrile [CH3CN] from 9/1 to 0/10 with 0.1% of TFA) delivered the corresponding Mito10-NAC (0.15 g, 83% yield). [00144] HRMS calculated for Mito10-NAC C33H44N2O2PS+ [M]+ 563.2856, found, 563.2856. 31P NMR (400.13 MHz, CDCl3) δ 23.76. 1H NMR (400.13 MHz, CDCl3), δ 7.83- 7.77 (3H, m), 7.71-7.59 (12H, m), 7.44-7.37 (1H, m), 7.12-7.01 (1H, m), 6.90-6.75 (1H, m), 4.59-4.50 (1H, m), 3.25-3.08 (4H, m), 2.97-2.71 (2H, m), 2.01 (3H, s), 1.58-1.62 (3H, m), 1.52- 1.38 (4H, m), 1.26-1.16 (9H, m). 13C NMR (75 MHz, CDCl3) δ 171.2, 170.2, 135.4, 135.3, 133.4, 133.2, 130.7, 130.5, 118.4, 117.5, 55.2, 39.5, 30.2, 30.1, 28.9, 28.7, 28.6, 28.5, 28.3, 26.7, 26.4, 22.9, 22.4 (d, J = 4.4), 22.3 (d, J = 51.3).
MCW C2267 Attorney Docket No. 650053.01008 [00145] Synthesis of Mito10-NAC-SMe [00146] The mitochondria targeted N-acetyl methylated cysteine (Mito10-NAC-SMe) was prepared using the same reaction conditions as for the synthesis of Mito10-NAC. The synthesis of Mito10-NAC-SMe is shown in Scheme 4. Scheme 4. i, HOBt, DIC, (10-
aminodecyl)- CH2Cl2, rt., 12 h, 43%. [00147] A stirred solution of N-acetyl-S-methyl-L-cysteine (0.15 g, 0.75 mmol) in CH2Cl2/DMF (15 mL/100 mL) was cooled to 0°C and successively treated with HOBt (0.13 g, 0.96 mmol), DIC (152 µL, 0.96 mmol). After stirring for 2 h at room temperature, (10- aminodecyl)-triphenylphosphonium bromide hydrochloride (0.35 g, 0.65 mmol) and triethylamine (188 µL, 0.13 mmol) were added to the mixture. The reaction mixture was stirred overnight at room temperature. Then, CH2Cl2 was added to the mixture as well as H2O (25 mL). The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The crude product was poured in 100 mL of ether and centrifuged. The insoluble salt was collected and purified by reverse phase chromatography on a C18 column (H2O/CH3CN from 9/1 to 0/10 with 0.1% of TFA) and delivered the corresponding Mito10-NAC-SMe (0.18 g, 43% yield). [00148] HRMS calculated for Mito10-NAC-SMe C34H46N2O2PS+ [M]+ 577.3012, found, 577.3015. 31P NMR (400.13 MHz, CDCl3) δ 23.90. 1H NMR (400.13 MHz, CDCl3), δ 7.86- 7.80 (3H, m), 7.75-7.64 (12H, m), 7.19-7.06 (1H, m), 7.05-6.84 (1H, m), 4.58-4.48 (1H, m), 3.39-3.16 (4H, m), 2.89-2.82 (2H, m), 2.13 (3H, s), 2.04 (3H, s), 1.68-1.42 (6H, m), 1.32-1.19 (10H, m).13C NMR (75 MHz, CDCl3) δ 170.8, 170.7, 135.3, 135.2, 133.3, 133.2, 130.6, 130.5, 118.3, 117.5, 52.8, 39.5, 36.4, 30.2, 30.1, 26.5, 22.9, 22.4 (d, J = 51.4), 22.3 (d, J = 4.4), 15.7. [00149] Synthesis of Mito-PEG4-NAC [00150] The mitochondria-targeted pegylated N-acetylcysteine (Mito-PEG4-NAC) was prepared in three steps. Activation of the carboxylic acid by DIC/HOBt followed by the addition of the corresponding bromopegylated derivative in the presence of pyridine in CH2Cl2 led to the pegylated bromide derivative. The nucleophilic substitution of the bromide by the
MCW C2267 Attorney Docket No. 650053.01008 triphenylphosphine afforded the mitochondria-targeted intermediates. Deprotection of the thiol by TFA and triethylsilane delivered the Mito-PEG4-NAC. The synthesis of Mito-PEG4-NAC is shown in Scheme 5. [2-[2-
(2- rt., reflux, 48 h, 46%; iii, EtSi-H, TFA, rt., 1 h, 95%. [00151] A stirred solution of N-acetyl-S-trityl-L-cysteine (0.5 g, 1.2 mmol) in CH2Cl2 (10 mL) was cooled to 0°C and successively treated with HOBt (0.3 g, 2.4 mmol), DIC (390 µL, 2.4 mmol). After stirring for 2 h at room temperature, (2-[2-[2-(2- bromoethoxy)ethoxy]ethoxy]ethanol (0.28 g, 1.1 mmol) and pyridine (97 µL, 1.2 mmol) were added to the mixture. The reaction mixture was then stirred overnight at room temperature. Then, CH2Cl2 was added to the mixture as well as H2O (25 mL). The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (CH2Cl2 /EtOH 9/1) and led to the corresponding trityl-PEG- NAC (0.46 g, 58% yield). HPLC-MS indicated that the product was sufficiently pure and could be used without further purification. ESI-MS for trityl-PEG-NAC C32H38BrNO6S [MH]+, 645.0. A mixture of PEG-NAC (0.46 g, 0.7 mmol) and triphenylphosphine (0.2 g, 0.8 mmol) in CH3CN was refluxed for 48 h. The crude product was poured into ether. The insoluble salt was purified by flash chromatography (CH2Cl2/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. ESI-MS for trityl-Mito-PEG-NAC C50H53NO6PS+ [MH]+, 826.4. [00152] A mixture of trityl-Mito-PEG-NAC (0.2 g, 0.2 mmol), triethylsilane (a few drops), in trifluoroacetic acid (1 mL) and CH2Cl2 (1 mL) was stirred at room temperature for 1 h. Then, the mixture was purified directly by reverse phase chromatography on C18 column
MCW C2267 Attorney Docket No. 650053.01008 (H2O /CH3CN from 9/1 to 0/10 with 0.1% of TFA) delivered the corresponding Mito-PEG4- NAC (0.14 g, 96% yield). [00153] HRMS calculated for Mito-PEG4-NAC C31H39NO6PS+ [M]+ 584.2230, found, 584.2232. 31P NMR (400.13 MHz, CDCl3) δ 25.09. 1H NMR (400.13 MHz, CDCl3), δ 7.83- 7.63 (15H, m), 6.88-6.77 (1H, m), 6.71-6.62 (1H, m), 4.87-4.78 (1H, m), 4.44-4.19 (2H, m), 3.91-3.65 (6H, m), 3.58-3.52 (2H, m), 3.45-3.40 (2H, m), 3.33 (4H, s), 3.08-2.89 (2H, m), 2.05 (3H, s).13C NMR (75 MHz, CDCl3) δ 171.2, 170.1, 134.83, 134.81, 133.9, 133.8, 130.2, 130.0, 119.2, 118.3, 70.5, 70.3, 70.2, 70.0, 68.8, 64.5, 63.6, 63.5, 53.9, 26.7, 24.7 (d, J = 53.5), 22.9. [00154] Example 2. Synthesis of N-acetylcysteine amide (NACA) [00155] A generic synthesis of NACA is shown in Scheme 6.
i, HOBt, DIC, aminoalkyl, triethylamine, CH2Cl2, rt., 12h; ii, EtSi-H, TFA, rt., 1h; iii, HOBt, DIC, PEG-OH, pyridine, CH2Cl2, rt., 12h; iv, EtSi-H, TFA, rt., 1h; v, HOBt, DIC, PEG-NH2, triethylamine, CH2Cl2, rt., 12h ; vi, EtSi-H, TFA, rt., 1h. [00156] Example 3. Antiproliferative Effects of Mitochondria-Targeted N- acetylcysteine and Analogs in Cancer Cells [00157] The relative antiproliferative potencies of NAC, Mito10-NAC, and their methylated analogs in several cancer cells were compared. In particular, the results show that Mito10-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 half maximal inhibitory concentration [IC50] for Mito10-MeNAC is 1.9 µM compared with 9.6 µM for Mito10-NAC), indicating that the antiproliferative effect is not related to the antioxidant or radical scavenging mechanism. [00158] Antiproliferative effects of Mito10-NAC [00159] The effects of Mito10-NAC and NAC on the proliferation of several cancer cell lines derived from pancreatic, breast, and lung cancers (MiaPaCa-2, MDA-MB-231, MCF-7,
MCW C2267 Attorney Docket No. 650053.01008 and A549) and a nonmalignant breast cancer cell line (MCF-10A) as a control were determined. The effect of Mito10-NAC on the proliferation of MiaPaCa-2, MDA-MB-231, MCF-7, A549, and MCF-10A cells was tested. FIGS. 2A and 2B show the comparative effects of NAC and Mito10-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). Surprisingly, Mito10-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. One of the reasons for this considerable increase in the antiproliferative effects of Mito10-NAC may be related to the relative hydrophobicity difference between the untargeted and TPP+- conjugated analogs. Hydrophobicity calculations show that NAC is exceedingly hydrophilic, and Mito10-NAC is relatively more hydrophobic (log P values for NAC and Mito10-NAC are −0.7 and 6.4, respectively) (FIG.1B). [00160] To ensure that cell proliferation results were not affected by Mito-NAC degradation over the time course, results from cell proliferation experiments where Mito-NAC was added as a bolus or added freshly every 48 h were compared. No significant differences in cell proliferation profiles were observed, indicating that Mito-NAC remained relatively stable during the course of the experiment (FIG.9). [00161] Results also suggest that the NAC-induced antiproliferative effects observed at very high concentrations in cells may involve “off-target” effects and not mitochondria. Results obtained from oxygen consumption experiments in MiaPaCa-2 cells also support this conclusion (FIGS.6A-6B). Also, the MCF-10A cells that were used as a control nonmalignant cell line for breast cancer may not be an effective or proper nonmalignant cell line control for other types of cancer. [00162] The effects of methyl-substituted NAC and Mito10-NAC on the proliferation of human pancreatic cancer (MiaPaCa-2) cells were determined (FIGS.4A-4B). Results indicate that methylation of the sulfhydryl group actually enhanced the antiproliferative effect. This suggests that the antioxidant mechanism related to scavenging of reactive oxygen species (superoxide and hydrogen peroxide) or reactive nitrogen species (peroxynitrite) is probably not involved in the antiproliferative effects that Mito10-NAC (or its methylated analogs) induced in cancer cells. [00163] The effects of other NAC analogs (Mito-PEG4-NAC and NAC amide) on cell proliferation were also tested. The results show that the IC50 values at which Mito-PEG4-NAC
MCW C2267 Attorney Docket No. 650053.01008 and NAC amide to inhibit cell proliferation are 36.7 µM and 4300 µM, respectively (FIGS. 4A-4B). [00164] Both ATP (FIG. 5A) and cell toxicity, as revealed by the SYTOX Green assay (FIG. 5B), in MiaPaCa-2 cells in the presence of NAC and Mito10-NAC were monitored. At much higher concentrations (>50 mM), NAC inhibited ATP levels, but there was significant cell death under these conditions. At concentrations inhibiting human pancreatic cancer cell proliferations (i.e., 10–20 μM), Mito10-NAC had no effect on ATP or on cell death (FIGS.5A and 5B). [00165] Melanoma (UACC-62) cells behaved quite differently from other cancer cells. Melanoma cells were more resistant to NAC and Mito10-NAC, although Mito10-NAC was still much more potent than NAC. Another confounding aspect was that NAC exerted a dose- dependent biphasic effect (FIGS.8A-8B). Due to the experimental limitations of the assays, it was not practical to choose the same time point for cell proliferation or the Seahorse assay and ATP measurements (FIGS.4A, 4B, 5A, 5B, 6A, and 6B). [00166] The effect of NAC and Mito10-NAC on mitochondrial complex I-induced oxygen consumption [00167] Mitochondrial respiration (oxidative phosphorylation [OXPHOS]) and complex I-induced oxygen consumption were assessed using the Seahorse technique. MiaPaCa-2 cells were treated with varying concentrations of NAC and Mito10-NAC, and the overall oxygen consumption rate (OCR) was measured (FIG. 6A). The usual bioenergetic indices for mitochondrial stress were monitored. As shown, Mito10-NAC inhibited 50% of the basal OCR at the 20 µM level, whereas NAC required IC50 values at much higher concentrations (>100 mM) to inhibit the basal OCR. [00168] Because treatment with NAC over a 24 h time period caused considerable cell death (FIG. 5B), NAC or Mito10-NAC was tested to see if they could directly inhibit mitochondrial complex I-dependent OCR (FIG. 6B) by injecting NAC or Mito10-NAC into permeabilized cells in real time. Under these conditions, NAC inhibited only about 30% of complex I-induced oxygen consumption, even up to concentrations of 100 mM; direct cell toxicity is observed at such concentrations (FIG. 5B). In contrast, the IC50 value at which Mito10-NAC directly inhibits complex I-induced oxygen consumption is 37 µM. At this concentration of Mito10-NAC, there was negligible cell toxicity (FIG. 5B). Thiol-based antioxidants (NAC and glutathione [GSH] esters) induced transient mitochondrial oxidation and inhibition of the mitochondrial respiratory complex III in several cancer cells including glioblastoma. However, the present results using real-time monitoring of mitochondrial
MCW C2267 Attorney Docket No. 650053.01008 complex I-induced oxygen consumption indicate that NAC had no effect on mitochondrial respiration, even at high concentrations, in MiaPaCa-2 cells. [00169] The combined effect of NAC/Mito10-NAC and Mito10-NAC/MCT-1 inhibitor on pancreatic cancer cell proliferation [00170] Monocarboxylate transporter has been used as a therapeutic target in cancer cells. Previously, it was shown that simultaneous inhibition of monocarboxylate transporter 1 (MCT-1) and mitochondrial OXPHOS synergistically inhibited the proliferation of several cancer cells. More recently, these findings were confirmed in a B-cell lymphoma xenograft using AZD3965 and another OXPHOS inhibitor. NAC was reported to inhibit monocarboxylate transporter 4 (MCT-4) expression in cancer cell lines. NAC decreased MCT- 4 stromal expression that is used as a biomarker of breast cancer. Mito10-NAC may synergize with NAC. The synergistic effects of Mito10-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 Mito10-NAC and AZD3965 or NAC, independently and together, and cell growth was monitored continuously. These results, presented in FIGS.7A-7F, indicate that Mito10-NAC is synergistic with MCT-1 inhibitors (AZD3965) but not with NAC, as shown by the combination-index-fraction affected plots. [00171] Relative inhibitory effects of mitochondria-targeted drugs [00172] Increasing the aliphatic chain length in TPP+-conjugated molecules greatly enhanced the antiproliferative potencies in tumor cells. As shown in FIG. 3A, 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. Although many factors are responsible for the fold difference between the TPP+-modified drug and the unmodified drug, the hydrophobicity of the parent drug is a major factor. If the parent compound is very hydrophilic (NAC), TPP+ modification will likely induce a greater fold difference in antiproliferative effect and inhibition of mitochondrial respiration in tumor cells due to the more negative mitochondrial membrane potential of tumor cells as compared with normal cells. It has previously been shown that TPP+ incorporation to the mitochondria- targeted drug is essential for its mitochondrial accumulation and antiproliferative efficacy in cancer cells. [00173] Lack of radical scavenging mechanism
MCW C2267 Attorney Docket No. 650053.01008 [00174] The paradoxical effects of reactive oxygen species (e.g., superoxide and hydrogen peroxide) have previously been reported in cancer cells. Superoxide and hydrogen peroxide, at low levels, are reported to promote tumorigenesis and tumor progression, but at higher levels, these species induce cytotoxicity in tumor cells and inhibit metastasis. This suggests that reactive oxygen species inhibition will affect tumorigenesis, tumor progression, and metastasis differently. Redox modulators (NAC) and chain-breaking antioxidant-inhibiting lipid peroxidation (vitamin E) enhanced metastasis of lung cancer in mice. However, based on the results obtained with methylated Mito10-NAC, it can be concluded that the reactive oxygen species or redox modulating effects of Mito10-NAC are unlikely to play a key role in its antiproliferative mechanism. The IC50 value for Mito-NAC-SMe (lacking the –SH group) to inhibit cell proliferation (FIGS. 7A-7F) is similar or slightly lower than that of Mito-NAC (having the –SH group). Regardless of the presence or absence of the redox-sensitive –SH group, the antiproliferative effects of Mito-NAC and Mito-NAC-SMe are unaffected. Other studies have shown that blunting the nitroxide moiety (i.e., removing the superoxide dismutase mimetic mechanism) in Mito-CP did not affect its antiproliferative effect. Reactive oxygen species generation was also shown to be not responsible for the antiproliferative effects of TPP+-based mitochondria-targeted drugs in cancer cells. [00175] Immunomodulatory effects of NAC and anti-tumor immune function [00176] Recently, NAC has found new applications in immunotherapy. Chimeric antigen receptor (CAR) T cells are genetically modified T cells that will recognize and destroy a protein on cancer cells. CAR T cell therapy involves reprogramming a patient’s own T cells to recognize and attack a specific protein in cancer cells, and then infusing the T cells back into the patient. Often, enhanced oxidant-induced modifications in CAR T cells decrease this ability. NAC has been shown to improve the efficacy of adoptive T cell immunotherapy to treat melanoma. In a recent study, the NAC T cells were cultured before they were infused as immunotherapy in a preclinical model of melanoma; this resulted in an improved outcome. T cells treated with NAC were 33-fold more effective than those cultured without NAC. NAC improves the anti-tumor function of exhausted T cells, thereby enhancing therapeutic outcomes for adoptive cell transfer (ACT) therapy. NAC activates PI3K/Akt, inhibiting Foxo1, and inhibits reactive oxygen species, thereby enhancing the antitumor functionality of T cells. The NAC mediated opposing effect on T cells was dependent on the concentration. At low concentrations, NAC had an immunostimulatory effect, and at higher concentrations NAC had a suppressive effect. A Phase I clinical trial of NAC, which aims to optimize the metabolic tumor microenvironment, is ongoing. Although the bioavailability of NAC is low, it is
MCW C2267 Attorney Docket No. 650053.01008 membrane-permeable and has been shown to cross the blood–brain barrier in humans and rodents. [00177] Because Mito10-NAC is considerably more effective in tumor cells, the possibility of enhancing CAR-T cell therapy using Mito10-NAC may be explored. Published reports and an ongoing clinical trial using NAC attest to this possibility. Mitochondria-targeted drugs such as Mito-ATO reprogram the tumor microenvironment, inhibiting tumor-suppressive immune cells and activating T cells. Mito10-ATO could reverse immunosuppression by regulatory T cells by stimulating the function of effector T cells. Mito-ATO induced potent T cell immune responses in local and distant tumor sites, and it decreased myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Mito-ATO also increased tumor infiltrating CD4+ T cells. Mito-ATO improved the efficacy of PD-1 blockade immunotherapy. [00178] Synergistic antitumor effect of OXPHOS inhibitors and MCT-1/4 inhibitors [00179] The antiproliferative effect of Mito10-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. The combination therapy with mitochondria-targeted drugs is a promising option as it could significantly lower the concentration of AZD3965 used in cancer therapy. Other mitochondria-targeted drugs (i.e., metformin and phenformin) have been used in combination with AZD3965 in brain cancer studies. However, their effective concentrations were widely different. In this study, Mito10-NAC was used at low micromolar levels in combination with AZD3965 to achieve a synergistic inhibition in proliferation. [00180] The hyperpolarized [1-13C] NAC probe of the hyperpolarized 13C-MRI showed global distribution of NAC, including to the brain. This finding is consistent with previous studies that used isotopically substituted NAC56. Both tumor cell and mice xenograft studies showed that [13C] NAC forms a [13C] NAC–GSH dimer as well as other homodimers. Further, because no detectable levels of the levels of [13C] GSH were found, there is a possibility that NAC could induce GSH synthesis by an indirect mechanism. Additionally, it is suggested that a shortened relaxation time could be the reason no [13C] GSH was detected. Induction of GSH by NAC is cell dependent, and the mechanism by which GSH forms has yet to be determined.
MCW C2267 Attorney Docket No. 650053.01008 [00181] The cysteine residue, Cys90, in the ND3 subunit of mitochondrial complex I is reported to play a key role in mitochondrial function. Glutathionylation or nitrosation of this critical cysteine residue regulates redox signaling. Mito10-NAC could inhibit complex I by thiolation of mitochondrial cysteine proteome. However, 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. Previously, it was reported that mitochondria-targeted drugs (e.g., Mito-magnolol) decreased AKT and Foxo1 phosphorylation and induced cell cycle arrest in the G1 phase of the cell cycle. Future studies investigating the effect of NAC, Mito-NAC, and their methylated analogs on AKT signaling and cell cycle arrest in cancer cells should enhance our understanding of these redox-sensitive thiols. [00183] All the experiments were performed in different cancer cell lines. Based on the previous publications in which mitochondrial OXPHOS inhibitors were translated to in vivo mouse xenograft models, Mito10-NAC and analogs may show similar potency in mouse xenografts as well. Results indicate that Mito-NAC remained relatively stable over the time course in cell proliferation experiments. However, a comprehensive analytical study is required to monitor any oxidative degradation of compounds over the experimental duration. [00184] TPP+-conjugated analogs of NACA [00185] N-acetylcysteine amide (NACA), a more lipophilic, membrane-permeable and bloodbrain barrier permeant analog of the antioxidant thiol, NAC, was shown to be more potent than NAC in reversing paracetamol toxicity and oxidative stress-induced diseases (see Example 2). NACA was shown to enhance the therapeutic effect of neural stem cell-based antiglioma oncolytic virotherapy. Several analogs of NACA and Mito-NACA can be synthesized. These compounds can potentially enhance antitumor immune function. [00186] Although the invention has been described in considerable detail with reference to certain embodiments, one skilled in the art will appreciate that the present invention can be used in alternative embodiments to those described, which have been presented for purposes of illustration and not of limitation. Therefore, the scope of the appended claims should not be limited to the description of the embodiments contained herein. [00187] Methods
MCW C2267 Attorney Docket No. 650053.01008 [00188] The methods used in the synthesis, cell experiments, and statistical analysis of Mito10-NAC and its analogs follow standard scientific methods routinely used and described previously. [00189] Cancer Cell Lines. The following cell lines that were regularly authenticated were obtained from the American Tissue Culture Collection (Manassas, VA): 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. MCF-7 cells were maintained in MEM-α (Thermo Fisher Scientific, Cat# 12571) containing 10% fetal bovine serum. UACC- 62 cells were maintained in RPMI 1640 medium (Thermo Fisher Scientific, Cat# 11875) and supplemented with 10% fetal bovine serum. All cells were stored in liquid nitrogen and used within 20 passages after thawing. [00190] Cell proliferation measurements. The IncyCyte Live-Cell Analysis System was used to monitor cell proliferation. This imaging system is noninvasive and enables continuous monitoring of cell confluence over several days. In a 96-well plate, cells were plated at 1,000 cells per well in triplicates and left to adhere overnight. Cells were then treated with compounds tested at indicated concentrations, and the cell confluency was recorded over several days in the IncuCyte Live-Cell Analysis System. [00191] Intracellular ATP Levels. After seeding cells, overnight at 20,000 per well in 96-well plates, cells were exposed to NAC analogs for 24 h. A luciferase-based assay was used to measure intracellular ATP levels as per the manufacturer’s instructions (Cat# FLAA, Sigma Aldrich, St. Louis, MO). Briefly, an ATP assay mix solution consisting of luciferase and luciferin (Cat# FLAAM) was added to cell lysates. After swirling, the amount of light produced was immediately recorded in a luminometer. The results were normalized to the total protein level measured in each well, as determined Bradford method (Bio-Rad Laboratories, Hercules, CA). [00192] Mitochondrial Respiration Measurements. Mitochondrial oxygen consumption was measured in the Seahorse XF-96 Extracelluar Flux Analyzer (Agilent, North Billerica, MA). The bioenergetic function assay was used to determine the intact cell mitochondrial function of cells in response to drug treatment. After cells were treated with NAC or Mito10- NAC for 24 h, eight baseline OCR measurements were taken before injection of oligomycin (1
MCW C2267 Attorney Docket No. 650053.01008 mg/mL) to inhibit ATP synthase, dinitrophenol (50 µM) to uncouple the mitochondria and yield maximal OCR, and inhibitors of complexes I and III (1 µM rotenone and antimycin) to inhibit mitochondrial respiration. From these measurements, 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. P values of less than 0.05 were considered to be statistically significant. All values provided represent mean ± standard deviation. The number of replicates per treatment group are shown as n. The IC50 values and fitting curves were calculated using OriginPro 2016 (OriginLab Corporation, Northampton, MA). [00195] References 1. Schwalfenberg, G. K. N-Acetylcysteine: A review of clinical usefulness (an old drug with new tricks). J. Nutr. Metab.2021, 9949453. https:// doi. org/ 10.1155/ 2021/ 99494 53 (2021). 2. Schwaiger, T. A Review of the Use of N-Acetyl-Cysteine (NAC) in Clinical Practice, https:// www. natur almed icine journ al. com/ journ al/ review- use-n- acetyl- cyste ine- nac- clini cal- pract ice (2021). 3. Kwon, Y. Possible beneficial effects of N-acetylcysteine for treatment of triple- negative breast cancer. Antioxidants 10, 169. https:// doi. org/ 10. 3390/ antio x1002 0169 (2021). 4. Feng, H. et al. N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions. J. Exp. Clin. Cancer Res. 40, 133. https:// doi. org/ 10.1186/ s13046- 021- 01939-1 (2021). 5. Scheffel, M. J. et al. Efficacy of adoptive T-cell therapy is improved by treatment with the antioxidant N-acetyl cysteine, which limits activation-induced T-cell death. Cancer Res.76, 6006–6016. https:// doi. org/ 10.1158/ 0008- 5472. Can- 16- 0587 (2016). 6. Scheffel, M. J. et al. N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt- dependent manner. Cancer Immunol. Immunother. 67, 691–702. https:// doi. org/ 10. 1007/ s00262- 018- 2120-5 (2018).
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MCW C2267 Attorney Docket No. 650053.01008 41. Nakamura, H. & Takada, K. Reactive oxygen species in cancer: Current findings and future directions. Cancer Sci. 112, 3945–3952. https:// doi. org/ 10. 1111/ cas. 15068 (2021). 42. Sullivan, L. B. & Chandel, N. S. Mitochondrial reactive oxygen species and cancer. Cancer Metab.2, 17. https:// doi. org/ 10.1186/ 2049- 3002-2- 17 (2014). 43. Gill, J. G., Piskounova, E. & Morrison, S. J. Cancer, oxidative stress, and metastasis. Cold Spring Harb. Symp. Quant. Biol.81, 163–175. https:// doi. org/ 10.1101/ sqb. 2016.81.030791 (2016). 44. Kong, H. & Chandel, N. S. Regulation of redox balance in cancer and T cells. J. Biol. Chem.293, 7499–7507. https:// doi. org/ 10.1074/ jbc. TM117.000257 (2018). 45. Sayin, V. I. et al. Antioxidants accelerate lung cancer progression in mice. Sci. Transl. Med.6, 221ra215. https:// doi. org/ 10.1126/ scitr anslm ed.3007653 (2014). 46. Breau, M. et al. The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice. JCI Insight 4, e127647. https:// doi. org/ 10.1172/ jci. insig ht.127647 (2019). 47. Cheng, G. et al. Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bio-energetics and energy-sensing mechanism. Cancer Lett. 365, 96–106. https:// doi. org/ 10. 1016/j. canlet. 2015. 05. 016 (2015). 48. Cheng, G. et al. Potent inhibition of tumour cell proliferation and immunoregulatory function by mitochondria-targeted atovaquone. Sci. Rep.10, 17872. https:// doi. org/ 10.1038/ s41598- 020- 74808-0 (2020). 49. June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365. https:// doi. org/ 10. 1126/ scien ce. aar6711 (2018). 50. Sterner, R. C. & Sterner, R. M. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J.11, 69. https:// doi. org/ 10.1038/ s41408- 021- 00459-7 (2021). 51. Kalyanaraman, B. NAC, NAC, Knockin’ on Heaven’s door: Interpreting the mechanism of action of N-acetylcysteine in tumor and immune cells. Redox Biol.57, 102497. https:// doi. org/ 10.1016/j. redox.2022.102497 (2022). 52. Huang, M. et al. Prevention of tumor growth and dissemination by in situ vaccination with mitochondria-targeted atovaquone. Adv. Sci.9, 2101267. https:// doi. org/ 10. 1002/ advs.202101267 (2022).
MCW C2267 Attorney Docket No. 650053.01008 53. Pérez-Escuredo, J. et al. Monocarboxylate transporters in the brain and in cancer. Biochim. Biophys. Acta 1863, 2481–2497. https:// doi. org/ 10.1016/j. bbamcr.2016. 03.013 (2016). 54. Beloueche-Babari, M. et al. MCT1 Inhibitor AZD3965 increases mitochondrial metabolism, facilitating combination therapy and noninvasive magnetic resonance spectroscopy. Cancer Res. 77, 5913–5924. https:// doi. org/ 10. 1158/ 0008- 5472. Can- 16- 2686 (2017). 55. Yamamoto, K. et al. Real-Time insight into in vivo redox status utilizing hyperpolarized [1-(13)C] N-acetyl cysteine. Sci. Rep. 11, 12155. https:// doi. org/ 10. 1038/ s41598- 021- 90921-0 (2021). 56. Lauterburg, B. H., Corcoran, G. B. & Mitchell, J. R. Mechanism of action of N- acetylcysteine in the protection against the hepa-totoxicity of acetaminophen in rats in vivo. J. Clin. Invest.71, 980–991. https:// doi. org/ 10.1172/ jci110853 (1983). 57. Onukwufor, J. O. et al. A reversible mitochondrial complex I thiol switch mediates hypoxic avoidance behavior in C. elegans. Nat. Commun.13, 2403. https:// doi. org/ 10.1038/ s41467- 022- 30169-y (2022). 58. Go, Y. M., Chandler, J. D. & Jones, D. P. The cysteine proteome. Free Radic. Biol. Med.84, 227–245. https:// doi. org/ 10.1016/j. freer adbio med.2015.03.022 (2015). 59. AbuEid, M. et al. Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate mela-noma progression. iScience 24, 102653. https://doi.org/10.1016/j.isci.2021.102653 (2021). 60. Boyle, K. A. et al. Mitochondria-targeted drugs stimulate mitophagy and abrogate colon cancer cell proliferation. J. Biol. Chem.293, 14891–14904. https:// doi. org/ 10. 1074/ jbc. RA117.001469 (2018). 61. K. Sunitha, M. Hemshekhar, R.M. Thushara, M.S. Santhosh, M. Yariswamy, K. Kemparaju, K.S. Girish, N-Acetylcysteine amide: a derivative to fulfill the promises of N- Acetylcysteine, Free Radic Res 47(5) (2013) 357-67. 62. A. Khayyat, S. Tobwala, M. Hart, N. Ercal, N-acetylcysteine amide, a promising antidote for acetaminophen toxicity, Toxicol Lett 241 (2016) 133-42. 63. Y. Maddirala, S. Tobwala, H. Karacal, N. Ercal, Prevention and reversal of selenite-induced cataracts by N-acetylcysteine amide in Wistar rats, BMC Ophthalmol 17(1) (2017) 54.
MCW C2267 Attorney Docket No. 650053.01008 64. C.K. Kim, A.U. Ahmed, B. Auffinger, I.V. Ulasov, A.L. Tobias, K.S. Moon, M.S. Lesniak, N-acetylcysteine amide augments the therapeutic effect of neural stem cell- based antiglioma oncolytic virotherapy, Mol Ther 21(11) (2013) 2063-73. [00196] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses: [00197] Clause 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof wherein
R1 is H, C1-C4 ; R2 is H or C1-C4
W is NH, O, or S, L is C1-C20 alkylene, C2-C20 alkenylene, L1-RA-L2, or amino acid; L1 and L2 are each independently absent or C1-C10 alkylene; RA is –(CH2CH2O)q–, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently CF3, Me, Cl, OMe, C(O)CH3, NO2, 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-mercapto-N-ethylpropanamide.
MCW C2267 Attorney Docket No. 650053.01008 [00198] Clause 2. The compound of clause 1, or a pharmaceutically acceptable salt . of clause 2, or a pharmaceutically acceptable salt
R2 is H, and W is NH or O. [00200] Clause 4. The compound of clause 3, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-a) a) wherein n is 1-
[00201] Clause 5. The compound of clause 3, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-b) b) wherein n is
[00202] Clause 6. The compound of any one of clauses 1-5, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
MCW C2267 Attorney Docket No. 650053.01008 [00203] Clause 7. The compound of clause 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H or C1-C4 alkyl; R2 is H; and W is NH or O. [00204] 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. [00205] 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. The compound of clause 1, or a pharmaceutically acceptable salt thereof, which is isotopically labeled. [00207] Clause 11. The compound of clause 10, or a pharmaceutically acceptable salt thereof, wherein the compound is 13C labeled. [00208] Clause 12. The compound of clause 11, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (I-f) f). [00209] Clause 13.
the compound is , wherein n is 1-20.
[00210] 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. [00211] Clause 15. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of clauses 1-13, or a pharmaceutically acceptable salt thereof.
MCW C2267 Attorney Docket No. 650053.01008 [00212] Clause 16. The method of clause 15, wherein the cancer is pancreatic cancer, breast cancer, melanoma cancer, non-small cell lung cancer, or a combination thereof. [00213] Clause 17. The method of any one of clauses 15-16, further comprising administering to the subject an additional therapeutic agent. [00214] Clause 18. The method of clause 17, wherein the additional therapeutic agent is AZD3965. [00215] Clause 19. A method of enhancing CAR-T cell therapy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of clauses 1-13, or a pharmaceutically acceptable salt thereof. [00216] Clause 20. The method of clause 19, wherein the subject is a cell or a human. [00217] 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. [00218] Clause 22. The method of clause 20, wherein the subject is a human, and wherein 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. [00219] 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. [00220] Clause 24. The method of clause 23, wherein the sample comprises a cell. [00221] Clause 25. The method of any one of clauses 23-24, wherein analyzing the labeled sample comprises analyzing a profile or an image of the labeled sample. [00222] Clause 26. The method of clause 25, wherein analyzing the labeled sample comprises analyzing the profile of the labeled sample. [00223] Clause 27. The method of clause 26, wherein the profile comprises a proteomic profile. [00224] Clause 28. The method of clause 27, comprising analyzing the proteomic profile of the labeled sample using mass spectrometry. [00225] Clause 29. The method of clause 25, wherein analyzing the labeled sample comprises analyzing the image of the labeled sample.
MCW C2267 Attorney Docket No. 650053.01008 [00226] Clause 30. The method of clause 23, comprising generating the image of the labeled sample using magnetic resonance imaging (MRI).
Claims
MCW C2267 Attorney Docket No. 650053.01008 CLAIMS 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof wherein
R1 is H, C1-C4 ; R2 is H or C1-C4
W is NH, O, or S, L is C1-C20 alkylene, C2-C20 alkenylene, L1-RA-L2, or amino acid; L1 and L2 are each independently absent or C1-C10 alkylene; RA is –(CH2CH2O)q–, arylene, or cycloalkylene; q is 1-20; X is a counterion; Y at each occurrence is independently CF3, Me, Cl, OMe, C(O)CH3, NO2, 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-mercapto-N-ethylpropanamide.
MCW C2267 Attorney Docket No. 650053.01008 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is .
of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is H, and W is NH or O. 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-a) a) wherein n is 1-
5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, having a structure of formula (I-b) b)
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
MCW C2267 Attorney Docket No. 650053.01008 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is H or C1-C4 alkyl; R2 is H; and W is NH or O. 8. The compound of claim 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. 9. The compound of claim 1, which is selected from the group consisting of ,
MCW C2267 Attorney Docket No. 650053.01008
10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is isotopically labeled. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound is 13C labeled. 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (I-f) f). 13. The compound of
,
wherein n is 1-20. 14. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
MCW C2267 Attorney Docket No. 650053.01008 15. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 16. The method of claim 15, wherein the cancer is pancreatic cancer, breast cancer, melanoma cancer, non-small cell lung cancer, or a combination thereof. 17. The method of claim 15, further comprising administering to the subject an additional therapeutic agent. 18. The method of claim 17, wherein the additional therapeutic agent is AZD3965. 19. A method of enhancing CAR-T cell therapy in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 20. The method of claim 19, wherein the subject is a cell or a human. 21. The method of claim 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. 22. The method of claim 20, wherein the subject is a human, and wherein 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. 23. A method of analyzing a sample, the method comprising: contacting the sample with an isotopically labeled compound of claim 1, or a pharmaceutically acceptable salt thereof, thereby producing a labeled sample, and analyzing the labeled sample. 24. The method of claims 23, wherein the sample comprises a cell. 25. The method of claim 23, wherein analyzing the labeled sample comprises analyzing a profile or an image of the labeled sample. 26. The method of claim 25, wherein analyzing the labeled sample comprises analyzing the profile of the labeled sample.
MCW C2267 Attorney Docket No. 650053.01008 27. The method of claim 26, wherein the profile comprises a proteomic profile. 28. The method of claim 27, comprising analyzing the proteomic profile of the labeled sample using mass spectrometry. 29. The method of claim 25, wherein analyzing the labeled sample comprises analyzing the image of the labeled sample. 30. The method of claim 23, comprising generating the image of the labeled sample using magnetic resonance imaging (MRI).
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