CN117794533A - E3 ligase inhibitors and methods of use thereof - Google Patents

E3 ligase inhibitors and methods of use thereof Download PDF

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CN117794533A
CN117794533A CN202280055066.3A CN202280055066A CN117794533A CN 117794533 A CN117794533 A CN 117794533A CN 202280055066 A CN202280055066 A CN 202280055066A CN 117794533 A CN117794533 A CN 117794533A
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M·雷普
J·S·斯卡莱茨基
E·E·韦赫里
A·G·曼福德
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University of California
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University of California
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Priority claimed from PCT/US2022/033793 external-priority patent/WO2022266321A1/en
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Abstract

The present disclosure provides pharmaceutical compositions and drug delivery devices comprising a compound of formula I, II, III or IV. Methods of inhibiting E3 ligase activity are provided comprising contacting an E3 ligase with a compound of formula I, II, III, or IV. The present disclosure provides various therapeutic methods involving the administration of such compounds.

Description

E3 ligase inhibitors and methods of use thereof
Cross-reference to related patent applications
The present application claims the benefit of U.S. provisional patent application Ser. No. 63/211,868, filed on even 17 at 6, 2021, and U.S. provisional patent application Ser. No. 63/321,034, filed on even 17 at 3, 2022, which U.S. provisional patent application Ser. No. 63/211,868 and U.S. provisional patent application Ser. No. 63/321,034 are incorporated herein by reference in their entirety.
Incorporation by reference of sequence listing provided as text file
The sequence listing is provided with the present invention as a text file "BERK-447wo_seq_list_st25.txt" created at 2022, month 6, 7, and 12KB in size. The content of the text file is incorporated by reference in its entirety as part of the present invention.
Background
E3 ubiquitin ligases (more than 600 are known in humans) confer ubiquitinated substrate specificity, and because of their specificity for certain protein substrates, they are more attractive therapeutic targets than general proteasome inhibitors. Although the development of E3 ligands has proven challenging, recent development efforts have provided specific compounds that bind to a small number of E3 ligands. However, for most E3 ligases, the substrate binding site appears to be shallow and thus targeting with small molecules is difficult. In contrast, most small molecule drugs bind to enzymes or receptors in a tightly, well-defined pocket. Work in this area has found small molecules that can covalently interact with the E3 ligase resulting in irreversible interactions. These strong interactions often lead to adverse consequences, especially when used in the treatment of diseases. There is a need in the art for safe and reversible inhibitors of E3 ligase small molecules.
Disclosure of Invention
The present disclosure provides pharmaceutical compositions and drug delivery devices comprising a compound of formula I, II, III or IV. Methods of inhibiting E3 ligase activity are provided comprising contacting an E3 ligase with a compound of formula I, II, III, or IV. The present disclosure provides various therapeutic methods involving the administration of such compounds.
Drawings
Fig. 1 provides structures of example compounds and 50% inhibitory effective concentrations (EC 50) of these compounds to inhibit Fem1 b.
FIGS. 2A-2N show the results of secondary compound screening.
FIG. 3 provides structures of exemplary compounds and EC50 values for the compounds.
The structures of the exemplary compounds and EC50 values for Fem1b inhibition are provided in fig. 4.
Definition of the definition
The term "linker" or "connecting" as used herein refers to a linking moiety that connects two groups and has a backbone length of 100 atoms or less. The linker or linkage may be a covalent bond linking two groups, or a chain between 1 and 100 atoms in length, for example a chain of 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18 or 20 carbon atoms in length, wherein the linker may be a straight chain, branched, cyclic or a single atom. In some cases, one, two, three, four, or five or more carbon atoms of the linker backbone may be optionally substituted with sulfur, nitrogen, or oxygen heteroatoms. The bond between the backbone atoms may be saturated or unsaturated, typically no more than one, two or three of the unsaturated bonds in the linker backbone. The linker may include one or more substituents, such as alkyl, aryl or alkenyl. The linker may include, but is not limited to, polyethylene glycol; ethers, thioethers, tertiary amines, alkyl groups, which may be straight or branched chain methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (t-butyl) and the like. The linker backbone may comprise a cyclic group, such as an aryl, heterocyclic or cycloalkyl group, wherein 2 or more atoms, such as 2, 3 or 4 atoms, of the cyclic group are included in the backbone. The linker may be a cleavable or non-cleavable linker.
In the present invention, the terms "treatment", "treatment" and the like refer to achieving a desired pharmacological and/or physiological effect. The effect may be a prophylactic effect in terms of completely or partially preventing a disease or symptom thereof, and/or may be a therapeutic effect in terms of partially or completely curing a disease and/or adverse effects due to the disease. "treatment" as used herein encompasses any treatment of a disease in a mammal (e.g., a human) and includes: (a) Preventing a disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., arresting its development; (c) alleviating the disease, even if the disease resolves.
The terms "individual," "subject," "host," and "patient" are used interchangeably herein to refer to an individual organism, such as a mammal, including, but not limited to, murine, ape, human, non-human primate, mammalian farm animal, mammalian sport animal, and mammalian pet.
The term "binding" refers to a direct association between two molecules, for example, due to covalent, electrostatic, hydrophobic, and ionic and/or hydrogen bond interactions, including salt and water bridge interactions, and the like.
The term "inhibitor" refers to a compound having the ability to inhibit a biological function of a protein of interest or a biological process of interest. When inhibiting a target protein, the inhibitor can inhibit the activity of the target protein.
The term "simultaneous" or "simultaneously" when administering compounds to a subject refers to the administration of one or more compounds at the same time or at two different time points separated by no more than 1 hour.
The term "sequentially" refers to administration of more than one compound at two different time points separated by more than 1 hour (e.g., about 2 hours, about 5 hours, 8 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more).
Some chemical groups named in the present invention may be preceded by a shorthand designation that indicates the total number of carbon atoms to be found in the indicated chemical group. For example, C7-C12 alkyl describes alkyl groups having a total of 7 to 12 carbon atoms as defined below; C4-C12 cycloalkylalkyl describes cycloalkylalkyl groups having a total of 4 to 12 carbon atoms as defined below. The total number of carbon atoms in the shorthand notation does not include carbon atoms that may be present in the group substituent.
In addition to the foregoing, the following terms have the meanings indicated, unless otherwise indicated: "amino" means-NH 2 And (3) free radicals. "cyano" refers to the-CN radical. "hydroxy" refers to an-OH radical. "imino" refers to the ═ NH substituent. "nitro" means-NO 2 And (3) free radicals. "oxo" refers to the ═ O substituent. "thioketone" refers to the ═ S substituent. "trifluoromethyl" means-CF 3 And (3) free radicals.
"alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, free of unsaturation, having 1 to 12 carbon atoms, for example 1 to 8 carbon atoms or1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond (e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc.). Unless specifically stated otherwise in the specification, alkyl groups may optionally be substituted with one of the following groups: alkyl, thiol, acyl alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, oxo, trimethylsilyl, -OR 14, -OC (O) -R14, -N (R14) 2, -C (O) R14, -C (O) OR14, -C (O) N (R14) 2, -N (R14) C (O) OR16, -N (R14) C (O) R16, -N (R14) S (O) tR16 (where t is 1-2), -S (O) tOR16 (where t is 1-2), -S (O) pR16 (where p is 0-2), and-S (O) tN (R14) 2 (where t is 1-2), where each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, OR heteroarylalkyl; each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
"alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a group, consisting of carbon, hydrogen only, free of unsaturation, having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butene, and the like. The alkylene chain is linked to the remainder of the molecule by a single bond and to the group by a single bond. The point of attachment of the alkylene chain to the remainder of the molecule and the group may be through one or any two carbons in the chain. Unless specifically stated otherwise in the specification, the alkylene chain may be optionally substituted with one of the following groups: alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, oxo, trimethylsilyl, -OR 14, -OC (O) -R14, -N (R14) 2, -C (O) R14, -C (O) OR14, -C (O) N (R14) 2, -N (R14) C (O) OR16, -N (R14) C (O) R16, -N (R14) S (O) tR16 (where t is 1-2), -S (O) tmor 16 (where t is 1-2), -S (O) pR16 (where p is 0-2), and-S (O) tN (R14) 2 (where t is 1-2), wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, OR heteroarylalkyl; each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
"aryl" refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of this disclosure, an aromatic hydrocarbon group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Aromatic hydrocarbon groups include, but are not limited to, those selected from the group consisting of acetamimene, acenaphthylene, acephenanthrene, anthracene, azulene, benzene,Fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenalene, phenanthrene, obsidiene, pyrene, and benzophenanthrene-derived aromatic hydrocarbon groups. Unless specifically stated otherwise in the specification, the term "aryl" or the prefix "ar-" (e.g., "ar-" in "aralkyl") is intended to include aromatic hydrocarbon groups optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, thiol, acyl alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, aralkyl, heteroaryl, heteroaralkyl,-R15-OR 14, -R15-OC (O) -R14, -R15-N (R14) 2, -R15-C (O) R14, -R15-C (O) OR14, -R15-C (O) N (R14) 2, -R15-N (R14) C (O) OR16, -R15-N (R14) C (O) R16, -R15-N (R14) S (O) tR16 (wherein t is 1-2), -R15-N ═ C (OR 14) R14, -R15-S (O) tmor 16 (wherein t is 1-2), -R15-S (O) pR16 (wherein p is 0-2) and-R15-S (O) tN (R14) 2 (wherein t is 1-2), wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclylalkyl, heteroaryl OR heteroarylalkyl; each R15 is independently a direct bond or a linear or branched alkylene or alkenylene chain; each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
"aralkyl" refers to a radical of the formula-Rb-Rc, where Rb is an alkylene chain as defined above and Rc is one or more aromatic hydrocarbon groups as defined above, e.g., benzyl, benzhydryl, etc. The alkylene chain portion of the aralkyl radical may optionally be substituted with an alkylene chain, as described above. The aryl portion of the aralkyl radical may optionally be substituted with aryl groups, as described above.
"cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon and hydrogen atoms (which may include fused or bridged ring systems), having 3 to 15 carbon atoms, or having 3 to 10 carbon atoms, saturated or unsaturated, and attached to the remainder of the molecule by a single bond. Monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic radicals include adamantyl, norbornyl, decalinyl, and the like. Unless specifically stated otherwise in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals optionally substituted with one or more substituents independently selected from the group consisting of: alkyl, acyl, thiol, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heteroaralkyl, -R15-OR 14, -R15-OC (O) -R14, -R15-N (R14) 2, -R15-C (O) R14, -R15-C (O) OR14, -R15-C (O) N (R14) 2, -R15-N (R14) C (O) OR16, -R15-N (R14) C (O) R16, -R14) S (O) tR16 (wherein t is 1-2), -R15-N ═ C (OR 14) R14, -R15-S (O) tOR16 (wherein t is 1-2), -R15-S (O) 16 (wherein p is 0-2) and-R15-S (R14) C (O) OR16, -R14) R14 is independently of each other, cycloalkyl, heteroaryl, cycloalkyl, aryl, heteroaryl, cycloalkyl OR each heteroaryl; each R15 is independently a direct bond or a linear or branched alkylene or alkenylene chain; each R16 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
"halo" refers to bromine, chlorine, fluorine or iodine.
"haloalkyl" means an alkyl radical as defined above substituted with one or more halo radicals, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl and the like. The alkyl portion of the haloalkyl radical may optionally be substituted with alkyl groups, as described above.
"heterocyclyl" means a stable 3-18 membered non-aromatic ring radical consisting of 2-12 carbon atoms and 1-6 heteroatoms selected from the group consisting of: nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the specification, the heterocyclyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl group may optionally be oxidized; optionally quaternizing the nitrogen atom; the heterocyclyl groups may be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1,3] dithianthraquinone, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxo-1, 3-dioxolan-4-yl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinolinyl, thiazolidinyl, tetrahydrofurfuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, and 1, 1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, the term "heterocyclyl" is intended to include heterocyclyl radicals as described above optionally substituted with one or more substituents selected from the group consisting of: alkyl, acyl, thiol-alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thio, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R15-OR 14, -R15-OC (O) -R14, -R15-N (R14) 2, -R15-C (O) OR14, -R15-C (O) N (R14) 2, -R15-N (R14) C (O) OR16, -R15-N (R14) C (O) R16, -R15-N (R14) S (O) tR16 (where t is 1-2), -R15-N ═ C (OR 14) R14, -R15-S (O) tOR16 (where t is 1-2), -R15-S (O) 16 (where p is 0-R14) and where t is 1-S (O) t2), wherein each R14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, OR heteroarylalkyl; each R15 is independently a direct bond or a linear or branched alkylene or alkenylene chain; each R16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
"N-heterocyclyl" refers to a heterocyclyl radical as described above containing at least one nitrogen, the point of attachment of the heterocyclyl radical to the remainder of the molecule being through one nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical may optionally be substituted with a heterocyclyl radical, as described above.
"heterocycloalkyl" refers to a radical of formula-RbRh, wherein Rb is an alkylene chain as defined above, rh is a heterocyclyl radical as defined above, and if the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene chain at a nitrogen atom. The alkylene chain of the heterocycloalkyl radical may be optionally substituted with an alkylene chain, as described above. The heterocyclyl portion of the heterocycloalkyl radical may be optionally substituted with a heterocyclyl group, as described above.
"heteroaryl" means a 5-14 membered ring system radical comprising a hydrogen atom, 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of the present disclosure, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxanyl, benzofuranyl, benzoxazolyl benzothiazolyl, benzothiadiazolyl, benzo [ b ] [1,4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxanyl, benzodioxolyl, benzofuranyl, benzodioxanyl, benzobicyclon-containing, or (i.e., a) a mixture of the above-mentioned compounds benzodioxanyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazole, benzo [4,6] imidazo [1,2-a ] pyridinyl, carbazolyl, cinnamyl, dibenzofuranyl, dibenzothiaphenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, and isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxopyridyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrazolyl, pyridyl, pyrrolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quininyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, thiophene, benzothiophentriazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl)). Unless specifically stated otherwise in the specification, the term "heteroaryl" is intended to include heteroaryl radicals as described above optionally substituted with one or more substituents selected from the group consisting of: alkyl, acyl, thiol-alkenyl, alkoxy, ethoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thio, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R15-OR 14, -R15-OC (O) -R14, -R15-N (R14) 2, -R15-C (O) R14, -R15-C (O) OR14, -R15-C (O) N (R14) 2, -R15-N (R14) C (O) OR16, -R15-N (R14) C (O) R16, -R15-N (R14) S (O) tR16 (wherein t is 1-2), -R15-N ═ C (OR 14) R14, -R15-S (O) tOR16 (wherein t is 1-2), -R15-S (O) 16 (wherein p is 0-R15-S (O) and p is 1-2), wherein each is cycloalkyl, heteroaryl, cycloalkyl, OR each of which is independently selected from the group consisting of aryl, heteroaryl, aryl, cycloalkyl, and cycloalkyl; each R15 is independently a direct bond or a linear or branched alkylene or alkenylene chain; each R16 is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
"N-heteroaryl" refers to a heteroaryl radical as described above containing at least one nitrogen, the point of attachment of the heteroaryl radical to the remainder of the molecule being through one of the nitrogen atoms in the heteroaryl radical. The N-heteroaryl radical may optionally be substituted with a heteroaryl radical as described above.
"heteroaralkyl" refers to a radical of formula-RbRi, where Rb is an alkylene chain as defined above and Ri is a heteroaryl radical as defined above. The heteroaryl portion of the heteroarylalkyl radical may be optionally substituted with heteroaryl, as described above. The alkylene chain of the heteroaralkyl radical may optionally be substituted with an alkylene chain, as described above.
"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted and that the description includes both substituted and unsubstituted aryl groups. When a functional group is described as "optionally substituted," in turn, the substituents on the functional group are also "optionally substituted," and so on, such iterations are limited to five iterations, and in some cases, two iterations, for purposes of this disclosure.
"pharmaceutically acceptable carrier, diluent or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifying agent approved by the U.S. food and drug administration for use in humans or livestock.
"pharmaceutically acceptable salts" include both acid addition salts and base addition salts.
By "pharmaceutically acceptable acid addition salt" is meant a salt that retains the bioavailability and properties of the free base, has no adverse biological or other effects, and employs inorganic acids (such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like) and organic acids (such as, but not limited to, acetic acid, 2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxoglutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1, 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like).
By "pharmaceutically acceptable base addition salt" is meant a salt that retains the biological effectiveness and properties of the free acid without biologically or otherwise undesirable effects. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Examples of suitable inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts extracted from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dantol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenetolylamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Examples of suitable organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
By "pharmaceutical composition" is meant a formulation consisting of a compound and a medium commonly accepted in the art for delivery of biologically active complexes to mammals, such as humans. Such a medium may include a pharmaceutically acceptable carrier, diluent or excipient.
By "therapeutically effective amount" is meant an amount of a compound that, when administered to a mammal (e.g., a human), is sufficient to treat the disease or disorder in the mammal (e.g., human) suffering from the disease or disorder. The amount of the compound that constitutes a "therapeutically effective amount" will vary with the compound, the disease or disorder and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and the present disclosure.
The compounds disclosed in the present invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers and other stereoisomeric forms, which may be defined as (R) -or (S) -, in terms of absolute stereochemistry, or (D) -or (L) -, in terms of amino acids. The compounds disclosed in the present invention are intended to include all such possible isomers and their racemic and optically pure forms. Optically active (+) and (-), (R) -and (S) -or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis or resolution of racemates (or racemates of salts or derivatives) from suitable optically pure precursors using chiral High Pressure Liquid Chromatography (HPLC). When the compounds of the present invention contain olefinic double bonds or other centers of geometric asymmetry, the compounds are intended to include both geometric isomers of E and Z unless otherwise specified. Likewise, a compound is also intended to include all tautomeric forms.
"stereoisomers" refers to compounds which are bound by the same bond from the same atom but have different three-dimensional structures and the three-dimensional structures are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.
Brackets are used in the substituents of the present invention to save space. Thus, the use of brackets in a substituent means that the group in the bracket is directly attached to the atom preceding the bracket.
The term "drug delivery device" is understood to include any type of apparatus, system or device intended to dispense a drug immediately to a human or non-human body. By "immediate dispensing" it is meant that the user does not need any necessary intermediate manipulation of the drug between its expulsion from the drug delivery device to the human or non-human body. Without limitation, typical examples of drug delivery devices are found in injection devices, inhalers, and gastric tube feeding systems. Also, without limitation, exemplary injection devices may include syringes, auto-injectors, injection pen devices, and spinal injection systems.
"ubiquitin ligase binding moiety" refers to a portion of a bifunctional compound that binds to ubiquitin ligases (e.g.E3 ligase).
"protein targeting moiety" refers to a portion of a bifunctional compound that binds to a protein of interest. When the ubiquitin ligase binding moiety is present, the protein targeting moiety can bring the protein of interest into proximity to the ubiquitin ligase, thereby resulting in ubiquitination and degradation of the protein of interest.
"adjunctive therapy" refers to the secondary treatment of a disease or disorder treated with a composition of the present disclosure (i.e., the secondary treatment following administration of a compound of formula I, II, III, or IV or a compound shown in fig. 1, 2, 3, or 4). Adjuvant therapy is often used to supplement the treatments currently in use in order to improve the therapeutic effect of an individual in need thereof relative to any monotherapy.
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, 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 be limiting of the particular embodiments, since the scope of the present invention will be limited only by the appended claims.
If a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. If a stated range includes one or both of the limits, the invention also includes ranges excluding either or both of those included limits.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning 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 also be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are incorporated.
It is noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an E3 ligase in a cell" includes a plurality of such E3 ligases in a plurality of cells, and reference to "a metabolic disorder" includes reference to one or more metabolic disorders known to those skilled in the art, equivalents thereof, and the like. It should also be noted that any optional elements may be excluded when the claims are drafted. Accordingly, this statement is intended to serve as antecedent basis for use of exclusive terminology such as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of embodiments related to the invention are specifically included in the present invention and disclosed in the present invention as if each such combination were individually and explicitly disclosed. Moreover, all subcombinations of the various embodiments, and elements thereof, are expressly contemplated and disclosed herein as if each such subcombination were individually and specifically disclosed.
The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such publication by virtue of prior invention. Furthermore, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
Detailed Description
The present disclosure provides compositions and delivery devices comprising: i) A compound of formula I, II, III or IV, or a compound shown in fig. 1, 2, 3 or 4; and ii) a pharmaceutically acceptable excipient. The present disclosure provides methods of inhibiting E3 ligase activity. The present disclosure provides methods and compositions for treating cancer. The present disclosure provides methods and compositions for treating mitochondrial disorders. The present disclosure provides methods and compositions for treating psychotic disorders. The present disclosure provides methods and compositions for targeted degradation of a protein of interest using PROTAC.
Composition and method for producing the same
The present disclosure provides a composition comprising: i) A compound of formula I, II, III or IV; and ii) a pharmaceutically acceptable excipient. The present disclosure provides a composition comprising: i) A compound as shown in fig. 1, 2, 3 or 4; and a pharmaceutically acceptable excipient. The compound of formula I, II, III or IV is non-covalently bound to an E3 ligase. In other words, the binding of the compound of formula I, II, III or IV to the E3 ligase is non-covalent and reversible. The compound shown in any one of fig. 1, 2, 3 and 4 is non-covalently bound to an E3 ligase. In other words, the binding of the compound shown in any one of figures 1, 2, 3 and 4 to the E3 ligase is non-covalent and reversible.
The compositions of the present disclosure may comprise, in addition to a compound of formula I, II, III or IV of the present disclosure or a compound as shown in any one of figures 1, 2, 3 and 4, one or more of the following: salts, e.g. NaCl, mgCl 2 、KCl、MgSO 4 Etc.; buffers such as tris buffer, N- (2-hydroxyethyl) piperazine-N' - (2-ethanesulfonic acid) (HEPES), 2- (N-morpholino) ethanesulfonic acid (MES), 2- (N-morpholino) ethanesulfonic acid sodium salt (MES), 3- (N-morpholino) propanesulfonic acid (MOPS), N-tris (hydroxymethyl) methyl-3-aminopropanesulfonic acid (TAPS), and the like; a solubilizing agent; detergents, for example, nonionic detergents such as tween-20; protease inhibitors; glycerol, and the like. In certain instances, the composition does not comprise dimethyl sulfoxide (DMSO).
The composition may comprise a pharmaceutically acceptable excipient, various of which are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients are described in a number of publications, for example, "leimington: pharmaceutical science and practice ", 19 th edition (1995) or latest edition, mark publishing company; gennaro (2000) "leimington: pharmaceutical science and practice ", 20 th edition, lippincott Williams & Wilkins; pharmaceutical dosage forms and drug delivery systems (1999) H.C.Ansel et al, 7 th edition, lippincott Williams & Wilkins; pharmaceutical excipients handbook (2000) A.H.Kibbe et al, 3 rd edition, american society of pharmacies. In some cases, the pharmaceutically acceptable excipient is not dimethyl sulfoxide (DMSO).
A pharmaceutical composition may comprise: a compound of formula I, II, III or IV or a compound as shown in any one of figures 1 to 4; and ii) a pharmaceutically acceptable excipient. In certain instances, the subject pharmaceutical compositions will be suitable for administration to a subject, e.g., the subject pharmaceutical compositions are sterile. For example, in certain embodiments, the subject pharmaceutical compositions will be suitable for administration to a human subject, e.g., the compositions are sterile and free of detectable pyrogens and/or other toxins.
The protein composition may comprise other ingredients such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. To approximate physiological conditions, the compositions may include pharmaceutically acceptable excipients, such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, hydrochloride, sulfate, solvates (e.g., mixed ion salts, water, organics), hydrates (e.g., water), and the like, as desired.
For example, the compositions may comprise aqueous solutions, powders, granules, tablets, pills, suppositories, capsules, suspensions, sprays and the like. The compositions may be formulated according to various routes of administration described below.
Suitable excipients (e.g. for oral formulations) include croscarmellose sodium (disintegrant), microcrystalline cellulose (filler), magnesium stearate (anti-adherent, lubricant), povidone (disintegrant), sodium starch glycolate (disintegrant), silicon dioxide and hydrocolloids (glidant, lubricant).
Suitable excipients include oral tablets of the compound of cluster 47, croscarmellose sodium, magnesium stearate, microcrystalline cellulose and sodium sulphate (sodium dodecyl sulphate; SDS) pyrazolyl heterocyclic core excipients.
Suitable excipients include the oxazolium core of cluster 75 compound, microcrystalline cellulose, docusate sodium, magnesium stearate, povidone and sodium starch glycolate with sulfone fraction excipients oral tablets.
Suitable excipients include sulfone-based excipient oral tablets of cluster 75 compounds including croscarmellose sodium, docusate sodium, microcrystalline cellulose, povidone, sodium benzoate, sodium starch glycolate, and stearic acid.
Suitable excipients include sodium chloride, polyethylene glycol (PEG), benzyl alcohol, sorbitol, sodium saccharin, sodium citrate, anhydrous citric acid, methyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol, maltodextrin, lactic acid and glyceryl triacetate.
Delivery instrument
The present disclosure provides a drug delivery device comprising the composition of the present disclosure. Suitable drug delivery devices include, but are not limited to, an injection device (e.g., a syringe, pen-type syringe, auto-injector, high-volume device, pump, infusion system, or other device configured for subcutaneous, intramuscular, or intravenous delivery); a skin patch (e.g., a permeation patch, a chemical patch, a microneedle patch); an inhaler (e.g., nasal or pulmonary); an implant device; and a gastrointestinal delivery system.
Methods of inhibiting E3 ligase activity
The present disclosure provides methods of inhibiting E3 ligase activity. The method comprises contacting an E3 ligase with a compound of the present disclosure. In some cases, the E3 ligase is present in the cells in vitro. In certain instances, the E3 ligase is present in the cell, tissue, organ, or extracellular body fluid of the individual.
E3 ligase is a complex of polypeptides. In some cases, the E3 ligase is a Cullin-RING ligase. In some cases, the E3 ligase is a CULE2 ligase.
In certain instances, compounds of the present disclosure may inhibit FEM1B polypeptides. In certain instances, the E3 ligase comprises a FEM1B polypeptide; for example, in some cases, the E3 ligase consists of CUL2, eloB/C, RBX1 and FEM 1B. FEM1B is a component of the E3 ligase that acts as a substrate recognition subunit.
In certain instances, the E3 ligase inhibitor is described by formula (I):
formula (I)
Wherein: x is selected from O, S or NH 2 The method comprises the steps of carrying out a first treatment on the surface of the In some cases, R 1 May be selected from aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, or substituted heteroaralkyl. In some cases, R 2 May be selected from alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, acyl, aminoacyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, or substituted heteroaralkyl. In some cases, R 3 、R 4 、R 5 、R 6 And R is 7 Each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano, or thiol. In some cases, R 1 Selected from thiophene, substituted thiophene, phenyl or substituted phenyl. In some cases, R 1 The description is made by the following structure:
wherein R is a Selected from hydrogen, hydroxy, fluoro, chloro, bromo or iodo,represents R 1 -a C bond. In some cases, R 2 Selected from alkyl, substituted alkyl, alkylaryl, substituted alkylaryl, C1-C8 straight chain alkyl, C1-C8 branched chain alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, octyl, benzyl, substituted benzyl, fluorine, chlorine, bromine or iodine. In some cases, R 5 Selected from hydrogen, fluorine, chlorine, bromine or iodine。
In certain instances, the E3 ligase inhibitor is described by formula (II):
formula (II)
Wherein: r is R 1 Selected from the group consisting of aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl. In some cases, R 1 Can be selected from phenyl, substituted phenyl, pyrazole, substituted pyrazole, N-ethyl-3-methylpyrazole, N-methyl-5-methylpyrazole, pyridine or thiophene.
In certain instances, the E3 ligase inhibitor is described by formula (III):
formula (III)
Wherein R is 1 Selected from alkyl, substituted alkyl, acyl alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In some cases, R 2 、R 3 、R 4 、R 5 、R 6 And R is 7 Selected from hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano or thiol. In some cases, R 1 Is represented by the following formula:
/>
wherein R is a Selected from C1-C8 alkyl, substituted C1-C8 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl or octyl,represents R 1 -N bond. In some cases, C1-C8 alkyl is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkylSubstituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl. In some cases, R a Is a C2 alkyl group substituted with a phenyl group. In some cases, R 3 Selected from hydroxy, alkoxy, methoxy, ethoxy, methyl or C1-C8 alkyl. In certain embodiments, R 4 Selected from hydroxy, alkoxy, methoxy, ethoxy, methyl or C1-C8 alkyl. In some cases, R 5 Selected from hydroxy, alkoxy, methoxy, ethoxy, methyl or C1-C8 alkyl.
In certain instances, the E3 ligase inhibitor is described by formula (IV):
(IV)
Wherein R is 1 Selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, thiophene, substituted phenyl, and o-methoxyphenyl. In some cases, R 1 Is represented by the following formula:
wherein,represents R 1 -a C bond. In certain cases, formula (IV) includes R 2 Hydroxy and R in position 5 Bromine in the position.
In certain instances, the E3 ligase comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to amino acids 1-627 of the following amino acids of the following human Fem1b amino acid sequence: MEGLAGYVYKAASEGKVLTLAALLLNRSESDIRYLLGYVSQQGGQRSTPLIIAARNGHAKVVRLLLEHYRVQTQQTGTVRFDGYVIDGATALWCAAGAGHFEVVKLLVSHGANVNHTTVTNSTPLRAACFDGRLDIVKYLVENNANISIANKYDNTCLMIAAYKGHTDVVRYLLEQRADPNAKAHCGATALHFAAEAGHIDIVKELIKWRAAIVVNGHGMTPLKVAAESCKADVVELLLSHADCDRRSRIEALELLGASFANDRENYDIIKTYHYLYLAMLERFQDGDNILEKEVLPPIHAYGNRTECRNPQELESIRQDRDALHMEGLIVRERILGADNIDVSHPIIYRGAVYADNMEFEQCIKLWLHALHLRQKGNRNTHKDLLRFAQVFSQMIHLNETVKAPDIECVLRCSVLEIEQSMNRVKNISDADVHNAMDNYECNLYTFLYLVCISTKTQCSEEDQCKINKQIYNLIHLDPRTREGFTLLHLAVNSNTPVDDFHTNDVCSFPNALVTKLLLDCGAEVNAVDNEGNSALHIIVQYNRPISDFLTLHSIIISLVEAGAHTDMTNKQNKTPLDKSTTGVSEILLKTQMKMSLKCLAARAVRANDINYQDQIPRTLEEFVGFH (SEQ ID NO: 1).
In certain instances, the E3 ligase comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% amino acid sequence identity to amino acids 1-627 of the following amino acids of the following mouse Fem1b amino acid sequence: MEGLAGYVYKAASEGKVLTLAALLLNRSESDIRYLLGYVSQQGGQRSTPLIIAARNGHAKVVRLLLEHYRVQTQQTGTVRFDGYVIDGATALWCAAGAGHFEVVKLLVSHGANVNHTTVTNSTPLRAACFDGRLDIVKYLVENNANISIANKYDNTCLMIAAYKGHTDVVRYLLEQRADPNAKAHCGATALHFAAEAGHIDIVKELIKWRAAIVVNGHGMTPLKVAAESCKADVVELLLSHADCDRRSRIEALELLGASFANDRENYDIMKTYHYLYLAMLERFQDGDNILEKEVLPPIHAYGNRTECRNPQELEAIRQDRDALHMEGLIVRERILGADNIDVSHPIIYRGAVYADNMEFEQCIKLWLHALHLRQKGNRNTHKDLLRFAQVFSQMIHLNEAVKAPDIECVLRCSVLEIEQSMNRVKNISDADVHSAMDNYECNLYTFLYLVCISTKTQCSEEDQCRINKQIYNLIHLDPRTREGFSLLHLAVNSNTPVDDFHTNDVCSFPNALVTKLLLDCGAEVNAVDNEGNSALHIIVQYNRPISDFLTLHSIIISLVEAGAHTDMTNKQNKTPLDKSTTGVSEILLKTQMKMSLKCLAARAVRANDINYQDQIPRTLEEFVGFH (SEQ ID NO: 2)
The subject compounds (e.g., compounds of any of formulas I, II, III, and IV; compounds shown in any of FIGS. 1-4) can inhibit E3 ligase activity by at least about 10% as compared to E3 ligase activity without contacting the compound. In certain instances, the subject compounds may inhibit E3 ligase activity by more than 10% as compared to E3 ligase activity that is not contacted with the compound. For example, a subject compound may inhibit E3 ligase activity by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100% as compared to E3 ligase activity that is not contacted with the compound.
In some cases, the E3 ligase is present in the cells in vitro. In some cases, the E3 ligase is present in the cells in vivo. In some cases, the cell is a cancer cell.
The assay described in the examples can be used to determine whether a compound inhibits the E3 ligase. For example, one has the following amino acid sequence: RNKSSLLFKESEETRTPNCNCKYCSHPVLG (SEQ ID NO: 3) and comprising a fluorescent-labeled polypeptide can be used as a substrate and contacted with E3 ligase in the presence or absence of the test compound to detect its inhibitory activity on E3 ligase. As another example, a degradation determinant reporter assay as described in the examples can be used to determine whether a compound inhibits an E3 ligase (e.g., FEM1B polypeptide). The decreased activity of the E3 ligase in the presence of the compound compared to the activity of the E3 ligase in the absence of the compound indicates that the compound inhibits E3 ligase activity.
Therapeutic method
The compounds of the present disclosure are useful in the treatment of various diseases and disorders. The present disclosure provides a method of selectively inhibiting E3 ligase activity in an individual, the method comprising administering to the individual an amount of a composition comprising: i) A compound of formula I, II, III or IV, or a compound as shown in any one of figures 1 to 4; and ii) a pharmaceutically acceptable excipient. An effective amount of a compound of formula I, II, III, or IV, or a compound as shown in any one of figures 1-4, is administered to selectively inhibit E3 ligase activity in the subject. In some cases, the subject compounds may inhibit E3 ligase activity by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100% as compared to E3 ligase activity that is not contacted with the compound.
In certain instances, the methods of treatment of the present disclosure comprise administering to an individual in need thereof a composition of the present disclosure. In certain instances, the methods of treatment of the present disclosure further comprise administering to an individual in need thereof a composition of the present disclosure in addition to an adjunctive therapy directed to treating the disorder.
Method for treating cancer
The present disclosure provides a method of treating cancer comprising administering to an individual an effective amount of a composition of the present disclosure. In some instances, an "effective amount" of a composition refers to an amount that reduces the number of cancer cells in an individual when one or more doses are administered to the individual in need thereof. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that, when administered to an individual in need thereof at one or more doses, reduces the number of cancer cells in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% as compared to the number of cancer cells in the individual prior to or without administration of the composition. In certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that reduces the number of cancer cells in an individual to undetectable levels when administered to the individual in need thereof at one or more doses.
In certain instances, an "effective amount" of a composition of the present disclosure means that the amount of a tumor in an individual can be reduced when one or more doses are administered to the individual in need thereof. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that, when administered to an individual in need thereof in one or more doses, reduces the tumor in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% as compared to the tumor in the individual prior to administration of the composition or when the composition is not administered. In certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that increases the survival time of an individual when one or more doses are administered to the individual in need thereof. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that increases the survival time of an individual by at least 1 month, at least 2 months, at least 3 months, 3 months to 6 months, 6 months to 1 year, 1 year to 2 years, 2 years to 5 years, 5 years to 10 years, or more when the composition of the present disclosure is administered to an individual in need thereof at one or more doses as compared to the expected survival time of the individual when the composition of the present disclosure is not administered.
In certain instances, adjunctive therapy is employed in addition to the compositions of the present disclosure to treat cancer in an individual in need thereof. In some cases, the adjuvant therapy regimen is selected from chemotherapy, hormonal therapy, immunotherapy, or targeted therapy. In addition to administering the compositions of the present disclosure, when chemotherapy is employed, various types of chemotherapeutic agents may be used. The types of chemotherapeutic agents useful in the methods of the present disclosure include, but are not limited to, alkylating agents, antimetabolites, anthracyclines, topoisomerase inhibitors, plant alkaloids, corticosteroids, and the like. The chemotherapy may employ any suitable alkylating agent including, but not limited to chlorambucil, cyclophosphamide, ifosfamide, millboard, and the like. Any suitable antimetabolite may be used in chemotherapy, including but not limited to 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), cytarabine, capecitabine, fludarabine, gemcitabine, methotrexate, pemetrexed, pravastatin, thioguanine, and the like. Any suitable anthracycline may be used in chemotherapy, including, but not limited to, doxorubicin, daunorubicin, idarubicin, epirubicin, and the like. Any suitable topoisomerase inhibitor may be used for chemotherapy, including but not limited to topotecan, irinotecan, etoposide, teniposide, and the like. Any suitable plant alkaloid may be used in chemotherapy, including but not limited to paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, and the like. Any suitable corticosteroid may be used in chemotherapy, including, but not limited to, prednisone, methylprednisolone, dexamethasone, and the like.
In addition to administering the compositions of the present disclosure, when hormone therapy is employed, a variety of hormone therapy drugs may be used. Hormone therapy drugs useful in the methods of the present disclosure include, but are not limited to, tamoxifen, letrozole, abiraterone, raloxifene, prednisone, and the like.
In addition to administering the compositions of the present disclosure, when immunotherapy is employed, a variety of immunotherapeutic drugs/monoclonal antibodies may be used. Immunotherapeutic drugs/monoclonal antibodies useful in the methods of the present disclosure include, but are not limited to, alemtuzumab, atilizumab, avilamab, ipilimumab, erltuzumab, ofatuzumab, na Wu Shankang, palbociclizumab, rituximab, dewaruzumab, mo Luoli mab, interferons, interleukins, and the like.
In addition to administering the compositions of the present disclosure, when targeted therapy is employed, a variety of drugs/monoclonal antibodies may be used. Targeted therapeutic/monoclonal antibodies useful in the methods of the present disclosure include, but are not limited to, imatinib, dasatinib, nilotinib, erlotinib, gefitinib, oritinib, olapanib, lu Kapa, nilapanib, tazopanib, ruxolitinib, phenanthridine, vitamin Mo Feini, dasatinib, kang Naifei, trimatinib, cobratinib, bimatinib, and the like.
Methods of treating metabolic disorders
The present disclosure provides methods of treating metabolic disorders. The methods generally involve administering to an individual suffering from a metabolic disorder an effective amount of a compound of the present disclosure.
Metabolic disorders treatable with the methods of the present disclosure include, but are not limited to, obesity, type 1 diabetes (T1D), type II diabetes, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatic steatosis.
In some instances, an "effective amount" of a composition refers to an amount that reduces the adverse symptoms in an individual when one or more doses are administered to the individual in need thereof. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that, when administered to an individual in need thereof in one or more doses, reduces at least one adverse symptom of a metabolic disorder in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% as compared to the symptom of the individual prior to or without administration of the composition. In certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that reduces an individual's adverse symptoms to undetectable levels when administered to an individual in need thereof at one or more doses. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that increases the survival time of an individual by at least 1 month, at least 2 months, at least 3 months, 3 months to 6 months, 6 months to 1 year, 1 year to 2 years, 2 years to 5 years, 5 years to 10 years, or more when the composition of the present disclosure is administered to an individual in need thereof at one or more doses as compared to the expected survival time of the individual when the composition of the present disclosure is not administered.
Subjects suitable for treatment using the methods of the present disclosure include individuals diagnosed with a metabolic disorder (e.g., type T1D, II diabetes, NAFLD, NASH, or hepatic steatosis). In some cases, the body mass index of the patient is greater than 30kg/m 2 。
In certain instances, adjunctive therapy is employed in addition to the compositions of the present disclosure to treat metabolic disorders in an individual in need thereof. The adjuvant therapy regimen may be directed to the disease or disorder being treated. Adjuvant therapy regimens useful in the present disclosure include, but are not limited to, insulin, glucagon, statins, thiazolidinediones, sulfonylureas, glinides, metformin, starch absorption blockers, incretin-based therapies, pramlintide, SGLT2 inhibitors, and the like. When insulin is used as the adjuvant therapy, any suitable insulin may be used, including but not limited to fast acting insulin, short acting insulin, medium acting insulin, long acting insulin, and the like. In some cases, the insulin administered is a combination of the above-described insulins. When a statin is used as an adjunct treatment, any suitable statin may be used including, but not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and the like. When thiazolidinediones are used as an adjunct treatment, any suitable thiazolidinedione may be used, including but not limited to rosiglitazone, pioglitazone, and the like. When sulfonylureas are used as an adjuvant therapy, any suitable sulfonylurea can be used, including but not limited to chlorpropamide, tolbutamide, glipizide, glibenclamide, glimepiride, and the like. When a glinide is used as an adjunctive therapeutic modality, any suitable glinide may be used, including but not limited to repaglinide, nateglinide, mitiglinide, and the like. When a starch absorption blocker is used as an adjunct treatment modality, any suitable starch absorption blocker may be used, including but not limited to acarbose, miglitol, and the like. When an incretin-based therapy is used as an adjunct treatment, any suitable incretin-based therapy may be used, including but not limited to sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, and the like. When an SGLT2 inhibitor is used as an adjunct therapy, any suitable SGLT2 inhibitor may be used, including but not limited to canagliflozin, dapagliflozin, enggliflozin, and the like.
Methods of treating mitochondrial disorders
The present disclosure provides methods and compositions for treating mitochondrial disorders. Mitochondrial diseases are often the result of deregulation of ATP production and oxidative/reductive stress. Mitochondrial diseases can also be caused by mutations (acquired or inherited) in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections or other environmental causes. Oxalate can enter cells known to cause mitochondrial dysfunction.
In particular embodiments, the methods are useful for treating mitochondrial disorders, including, for example, but not limited to, mitochondrial myopathy, diabetes and deafness (DAD), leber hereditary optic neuropathy, leigh syndrome, neuropathy, ataxia, retinitis, pigmentosis and ptosis (NARP), muscular-neuro-gastrointestinal-encephalopathy (MNGIE), myoclonus-type epilepsy with broken red fibers (MERRF), mitochondrial encephalomyopathy, hyperlactic and stroke-like episodes (MELAS), mitochondrial DNA depletion syndrome, muscular dystrophy, gericy, type 1 diabetes, type 2 diabetes, nonalcoholic fatty liver disease (NASH), nonalcoholic steatohepatitis (NASH), hepatic steatosis, lung adenocarcinoma, cancer, and the like. Other conditions and disorders that may be treated using the methods of the present disclosure include obesity, chronic fatigue syndrome, aging, hypercholesterolemia, heart disease, and cardiomyopathy.
Methods of treating psychotic disorders
The present disclosure provides a method of treating a psychotic disorder in an individual, the method comprising administering to the individual an effective amount of a composition of the present disclosure. In some instances, an "effective amount" of a composition refers to an amount that reduces the adverse symptoms in an individual when one or more doses are administered to the individual in need thereof. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that, when administered to an individual in need thereof in one or more doses, reduces the individual's adverse symptoms by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% as compared to the individual's adverse symptoms prior to or without administration of the composition. In certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that reduces an individual's adverse symptoms to undetectable levels when administered to an individual in need thereof at one or more doses. For example, in certain instances, an "effective amount" of a composition of the present disclosure refers to an amount that increases the survival time of an individual by at least 1 month, at least 2 months, at least 3 months, 3 months to 6 months, 6 months to 1 year, 1 year to 2 years, 2 years to 5 years, 5 years to 10 years, or more when the composition of the present disclosure is administered to an individual in need thereof at one or more doses as compared to the expected survival time of the individual when the composition of the present disclosure is not administered.
In particular embodiments, the methods are used to treat mitochondrial disorders, including, for example, but not limited to, alzheimer's disease, symptomatic mental disorders, schizophrenia, and the like.
In some cases, adjunctive therapy is used to treat a psychotic disorder in an individual in need thereof, in addition to the compositions of the present disclosure. The adjuvant therapy regimen may be directed to the disease or disorder being treated. Adjuvant therapy regimens useful in the present disclosure include, but are not limited to, cholinesterase, memantine, psychotropic drugs, and the like. When cholinesterase is used as the adjuvant therapy, any suitable cholinesterase may be used, including but not limited to donepezil, galantamine, rismin. When using a psychotropic drug as an adjunct treatment modality, any suitable psychotropic drug may be used, including but not limited to risperidone, carbamazepine, sodium valproate, lamotrigine, lithium carbonate, methylphenidate, propidine, aripiprazole, asenapine, bupropion Lei Pai, caliprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone, chlorpromazine, fluphenazine, haloperidol, perphenazine, and the like.
Subjects suitable for treatment
Subjects suitable for treatment using the methods of the present disclosure include cancer patients, including individuals who have been diagnosed with cancer, individuals who have received cancer treatment but who have not responded to treatment, and individuals who have received cancer treatment and who initially responded to treatment but subsequently remain refractory to the treatment without relief from the condition following treatment. Subjects suitable for treatment using the methods of the present disclosure include individuals with metabolic disorders, including individuals who have been diagnosed as having a metabolic disorder, as well as individuals who have received treatment for a metabolic disorder but who have not responded to the treatment. Subjects suitable for treatment using the methods of the present disclosure include individuals with a psychotic disorder, including individuals who have been diagnosed with a psychotic disorder, and individuals who have been treated for a psychotic disorder but have failed to respond to treatment.
Formulations
Suitable formulations are as described above, wherein suitable formulations include a pharmaceutically acceptable excipient. In some cases, suitable formulations include: a) A compound of formula I, II, III or IV of the present disclosure or a compound as shown in any one of figures 1-4; and b) a pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients are as described above.
Dosage of
The appropriate dosage may be determined by the attending physician or other qualified medical personnel based on various clinical factors. In the medical field, it is well known that the dosage of any patient depends on a number of factors, including the patient's body size, body surface area, age, the particular compound being administered, the patient's sex, time and route of administration, general health, and other drugs being administered simultaneously. The compositions of the present disclosure may be administered in unit doses of 1ng/kg body weight to 20mg/kg body weight, e.g., 0.1mg/kg body weight to 10mg/kg body weight, 0.5mg/kg body weight to 5mg/kg body weight; however, particularly in view of the above factors, it is also contemplated to use dosages below or above this exemplary range. If the regimen is continuous infusion, this range may also be 1 μg-10mg/kg body weight per minute. The compositions of the present disclosure may be administered in an amount of about 1mg/kg body weight to 50mg/kg body weight, for example, about 1mg/kg body weight to 5mg/kg body weight, about 5mg/kg body weight to about 10mg/kg body weight, about 10mg/kg body weight to about 15mg/kg body weight, about 15mg/kg body weight to about 20mg/kg body weight, about 20mg/kg body weight to about 25mg/kg body weight, about 25mg/kg body weight to about 30mg/kg body weight, about 30mg/kg body weight to about 35mg/kg body weight, about 35mg/kg body weight to about 40mg/kg body weight, or about 40mg/kg body weight to about 50mg/kg body weight.
In certain instances, suitable dosages of the compositions of the present disclosure are 0.01 μg to 100g/kg body weight, 0.1 μg to 10g/kg body weight, 1 μg to 1g/kg body weight, 10 μg to 100mg/kg body weight, 100 μg to 10mg/kg body weight, or 100 μg to 1mg/kg body weight. The dose repetition rate can be readily estimated by one of ordinary skill in the art based on the measured residence time and concentration of the administered agent in the body fluid or tissue. Preferably, after successful treatment, the patient is subjected to maintenance therapy to prevent disease recurrence, wherein the multimeric polypeptide of the present disclosure is administered at a maintenance dose in the range of 0.01 μg to 100g/kg body weight, 0.1 μg to 10g/kg body weight, 1 μg to 1g/kg body weight, 10 μg to 100mg/kg body weight, 100 μg to 10mg/kg body weight, or 100 μg to 1mg/kg body weight.
Those skilled in the art will readily appreciate that dosage levels may vary depending on the function of the specific compositions of the present disclosure, the severity of the symptoms, and the susceptibility of the subject to side effects. The preferred dosage of a given compound can be readily determined by one of skill in the art in a variety of ways.
In certain instances, multiple doses of the compositions of the present disclosure are administered. The frequency of administration of the compositions of the present disclosure may vary depending on any of a variety of factors, such as the severity of the symptoms, etc. For example, in certain instances, the compositions of the present disclosure are administered once a month, twice a month, three times a month, once every other week (qow), once a week (qw), twice a week (biw), three times a week (tiw), four times a week, five times a week, six times a week, once every other day (qod), once a day (qd), twice a day (qid), or three times a day (tid).
The duration of administration of the compositions of the present disclosure (e.g., the period of time of the compositions of the present disclosure) may vary depending on any of a variety of factors, such as patient response, etc. For example, the compositions of the present disclosure may be administered for a period of about one day to about one week, about two weeks to about four weeks, about one month to about two months, about two months to about four months, about four months to about six months, about six months to about eight months, about eight months to about one year, about one year to about two years, about two years to about four years, or more.
Route of administration
An active agent (a composition or compound of the present disclosure) is administered to a subject using any of the available methods and routes of drug delivery, including in vivo and in vitro methods, as well as systemic and topical routes of administration.
Conventional and pharmaceutically acceptable routes of administration include intratumoral, peritumoral, intramuscular, intratracheal, intracranial, subcutaneous, intradermal, topical application, intravenous, intraarterial, rectal, nasal, buccal and other enteral and parenteral routes of administration. The route of administration may be combined or modified (as desired) according to the compositions and/or desired effects of the present disclosure. The compositions of the present disclosure may be administered in a single dose or in multiple doses.
In certain instances, the compositions of the present disclosure are administered by intravenous injection. In certain instances, the compositions of the present disclosure are administered by intramuscular injection. In certain instances, the compositions of the present disclosure are administered topically. In certain instances, the compositions of the present disclosure are administered intratumorally. In certain instances, the compositions of the present disclosure are administered intratumorally. In certain instances, the compositions of the present disclosure are administered intracranially. In certain instances, the compositions of the present disclosure are administered subcutaneously.
The compositions of the present disclosure may be administered to a host using any of the available conventional methods and routes suitable for delivering conventional drugs, including systemic or topical routes. In general, routes of administration contemplated for use in one method of the invention include, but are not necessarily limited to, enteral, parenteral, and inhalation routes.
Parenteral routes of administration other than inhalation include, but are not necessarily limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intratumoral, peritumoral, and intravenous routes, i.e., any route of administration other than through the digestive tract. Systemic or local delivery of the compositions of the present disclosure may be effected by parenteral administration. If systemic delivery is desired, administration typically includes invasive or systemic absorption local or mucosal administration of the pharmaceutical formulation
PROTAC
The present disclosure provides a bifunctional compound for targeted degradation of a protein of interest.
One type of small molecule suitable for use in the present disclosure is a degradant molecule. Protein degradation targeting chimeras (PROTAC) technology utilizes small molecule recruitment of target proteins for ubiquitination and clearance by proteasomes (see Bondeson and Crews, small molecule targeting degradation proteins, pharmacological and toxicology annual book, day 6, 2017; 57:107-123; lai et al, modular PROTAC design for oncogenic BCR-ABL degradation, germany application chemistry, 2016, 11; 55 (2): 807-810; zhou et al, found a bromodomain and terminal ectodomain (BET) small molecule degradation agent with picomolar cellular potency and capable of tumor regression, journal of pharmaceutical chemistry, 2018, 61, 462-481).
PROTAC is a heterobifunctional small molecule with three chemical elements: a ligand that binds to a target protein, a ligand that binds to E3 ubiquitin ligase, and a linker for coupling the two ligands. PROTAC is a chemical knockdown strategy that degrades target proteins via ubiquitin-proteinase systems. Unlike the competitive and placeholder driven processes of traditional inhibitors, PROTAC is catalytic in its mode of action and can promote target protein degradation at low exposure.
The PROTAC molecule may also be referred to as a "bifunctional molecule". In certain aspects, the disclosure provides a bifunctional molecule comprising: i) A Fem1b E ubiquitin ligase binding moiety (ULM) (i.e., a ligand or "ULM" group for E3 ubiquitin ligase); and II) a Protein Targeting Moiety (PTM) (i.e., a protein/polypeptide targeting ligand or "PTM" group) attached directly or via a chemical linker, wherein ULM is a group according to the chemical structure of formula I, II, III or IV or a compound as shown in FIGS. 1-4, and PTM is a ligand that binds to a target polypeptide of target protein degradation.
Non-limiting examples of the invention
Various aspects (including embodiments) of the above-described subject matter may benefit alone or in combination with one or more other aspects or embodiments. Without limiting the above description, certain non-limiting aspects of the disclosure are provided below. It will be apparent to those skilled in the art after reading this disclosure that each of the independently numbered aspects can be used or combined with any of the independently numbered aspects either before or after. This is intended to provide support for a combination of all such aspects and is not limited to the combination of aspects explicitly provided below:
Aspect 1. A composition comprising:
a1 A compound of formula (I):
wherein:
x is O, S or NH;
R 1 is aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl;
R 2 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, acyl, aminoacyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl;
R 3 、R 4 、R 5 、R 6 and R is 7 Each independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitroAmino, hydroxy, cyano, thiol;
b1 A pharmaceutically acceptable excipient; or (b)
a2 A compound as shown in any one of figures 1 to 4; and
b2 A pharmaceutically acceptable excipient.
Aspect 2 the composition according to aspect 1, wherein R 1 Is thiophene or substituted thiophene.
Aspect 3 the composition according to aspect 1, wherein R 1 Is phenyl or substituted phenyl.
Aspect 4 the composition according to aspect 3, wherein R 1 The method comprises the following steps:
wherein R is a Is hydrogen, hydroxy or halogen
Wherein, Represents R 1 -a C bond.
Aspect 5 the composition according to aspect 4, wherein R a Is hydrogen or halogen selected from fluorine, chlorine, bromine or iodine.
Aspect 6 the composition according to any one of aspects 1 to 5, wherein R 2 Is alkyl, substituted alkyl, alkylaryl or substituted alkylaryl.
Aspect 7 the composition according to aspect 6, wherein R 2 Is a C1-C8 straight chain or C1-C8 branched alkyl group.
Aspect 8 the composition according to aspect 7, wherein R 2 Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, and octyl.
Aspect 9 the composition according to aspect 6, wherein R 2 Is benzyl or substituted benzyl.
Aspect 10 the composition according to aspect 9, wherein R 2 Is halogen substituted benzyl wherein the halogen is selected from fluorine, chlorine, bromine or iodine。
Aspect 11 the composition according to any one of aspects 1 to 5, wherein R 5 Is hydrogen or halogen selected from fluorine, chlorine, bromine or iodine.
Aspect 12. A composition comprising:
a compound of formula (II):
wherein R is 1 Is aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl; and
A pharmaceutically acceptable excipient.
Aspect 13 the composition of aspect 12, wherein R 1 Is phenyl or substituted phenyl.
Aspect 14 the composition of aspect 13, wherein R 1 Is a halogen substituted phenyl group, wherein the halogen is selected from fluorine, chlorine, bromine or iodine.
Aspect 15 the composition of aspect 12, wherein R 1 Is pyrazole or substituted pyrazole.
Aspect 16 the composition of aspect 15, wherein R 1 Is N-ethyl-3-methylpyrazole.
Aspect 17 the composition of aspect 15, wherein R 1 Is N-methyl-5-methylpyrazole.
Aspect 18 the composition of aspect 12, wherein R 1 Is pyridine.
Aspect 19 the composition of aspect 12, wherein R 1 Is thiophene.
In aspect 20, a composition comprises:
a compound of formula (III):
wherein:
R 1 is alkyl, substituted alkylAcyl, acyl alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R 2 、R 3 、R 4 、R 5 、R 6 and R is 7 Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano, and thiol; and
a pharmaceutically acceptable excipient.
Aspect 21 the composition of aspect 20, wherein R 7 Is hydrogen.
Aspect 22 the composition of aspect 20, wherein R 7 Is a nitro group.
Aspect 23 the composition of any one of aspects 20-22, wherein R 1 Is an acyl group.
Aspect 24 the composition of any one of aspects 23, wherein R 1 It is the result that the liquid crystal display device,
/>
wherein R is a Is C1-C8 alkyl or substituted C1-C8 alkyl, and
wherein,represents R 1 -N bond.
Aspect 25 the composition of aspect 24, wherein R a Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.
Aspect 26 the composition of aspect 24, wherein R a Is C1-C8 alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
Aspect 27 the composition of aspect 26, wherein R a Is a C2 alkyl group substituted with a phenyl group.
Aspect 28 the composition of any one of aspects 20-27, wherein R 3 Is a hydroxyl group.
Aspect 29 the composition of any one of aspects 20-27, wherein R 3 Is an alkoxy group.
Aspect 30 the composition of aspect 26, wherein R 3 Is methoxy or ethoxy.
Aspect 31 the composition of any one of aspects 20-27, wherein R 3 Is a C1-C8 alkyl group.
Aspect 32 the composition of aspect 31, wherein R 3 Is methyl.
Aspect 33 the composition of any one of aspects 20-32, wherein R 4 Is a hydroxyl group.
Aspect 34 the composition of any one of aspects 20-32, wherein R 4 Is an alkoxy group.
Aspect 35 the composition of aspect 34, wherein R 4 Is methoxy or ethoxy.
Aspect 36 the composition of any one of aspects 20-32, wherein R 4 Is a C1-C8 alkyl group.
Aspect 37 the composition of aspect 26, wherein R 4 Is methyl.
Aspect 38 the composition of any one of aspects 20-37, wherein R 5 Is a hydroxyl group.
Aspect 39 the composition according to any one of aspects 20 to 37, wherein R 5 Is an alkoxy group.
Aspect 40 the composition of aspect 39, wherein R 5 Is methoxy or ethoxy.
Aspect 41 the composition of any one of aspects 20-37, wherein R 5 Is a C1-C8 alkyl group.
Aspect 42 the composition of aspect 26, wherein R 5 Is methyl.
Aspect 43. A composition comprising:
a compound of formula (IV):
wherein:
R 1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R 2 、R 3 、R 4 、R 5 And R is 6 Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano, thiol, and colored alkoxide; and
a pharmaceutically acceptable excipient.
Aspect 44 the composition of aspect 43, wherein R 1 Is thiophene.
Aspect 45 the composition of aspect 43, wherein R 1 Is a substituted phenyl group.
Aspect 46 the composition of aspect 45, wherein R 1 Is o-methoxyphenyl.
Aspect 47 the composition of aspect 45, wherein R 1 The method comprises the following steps:
wherein,represents R 1 -a C bond.
Aspect 48. The composition of aspect 43, wherein:
R 2 is a hydroxyl group;
R 5 is bromine.
Aspect 49 the composition of aspect 43, wherein R 2 Is methyl mercaptan.
Aspect 50 the composition of any one of aspects 1-49, wherein the pharmaceutically acceptable excipient is not dimethyl sulfoxide.
Aspect 51 the composition of any one of aspects 1-50, wherein the composition is a sterile composition.
Aspect 52 a drug delivery device comprising the composition of any one of aspects 1-51.
Aspect 53 the drug delivery device of aspect 52, wherein said device comprises a syringe containing said composition.
Aspect 54 the drug delivery device of aspect 52, wherein the device comprises a pump.
Aspect 55. A method of inhibiting E3 ligase activity in a cell, the method comprising contacting the cell with a compound of formula I, II, III, or IV or a compound of any one of figures 1-4.
Aspect 56 the method of aspect 55, wherein the E3 ligase is Fem1b.
Aspect 57. The method of aspect 55 or aspect 56, wherein the cell is a cancer cell.
Aspect 58. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of the composition of any one of aspects 1-51.
Aspect 59 the method of aspect 58, wherein the cancer is lung adenocarcinoma.
Aspect 60 the method of aspect 58 or aspect 59, further comprising administering to the individual at least one additional cancer chemotherapeutic agent or anti-cancer polypeptide.
Aspect 61 the method of any one of aspects 58-60, wherein the composition is administered orally, intraperitoneally, intramuscularly, or intravenously.
Aspect 62. A method of treating a metabolic disorder in an individual, the method comprising administering to the individual an effective amount of the composition of any one of aspects 1-51.
Aspect 63. The method of aspect 62, wherein the metabolic disorder is diabetes.
Aspect 64 the method of aspect 63, wherein the diabetes is type 2 diabetes.
Aspect 65. The method of aspect 62, wherein the metabolic disorder is non-alcoholic fatty liver disease (NAFLD).
Aspect 66. The method of aspect 65, wherein the NAFLD comprises non-alcoholic steatohepatitis (NASH).
Aspect 67. The method of aspect 65, wherein the NAFLD comprises liver steatosis.
The method of any one of aspects 62-67, wherein the subject has a body mass index greater than 30kg/m 2 。
Aspect 69 the method of any one of aspects 62-68, wherein the composition is administered orally, intraperitoneally, intramuscularly, or intravenously.
Aspect 70 the method of any one of aspects 62-69, further comprising administering to the individual at least one additional agent that treats the metabolic disorder.
Aspect 71 the method of aspect 70, wherein the at least one additional agent is selected from the group consisting of insulin, glucagon, a statin, and a thiazolidinedione.
Aspect 72. A method of inhibiting proliferation of a cancer cell, the method comprising contacting the cell with a compound of formula I, II, III or IV or a compound as shown in any one of figures 1-4.
Aspect 73 a method of treating a psychotic disorder in a subject, the method comprising administering to the subject an effective amount of the composition of any of aspects 1-51.
Aspect 74 the method of aspect 73, wherein the mental disorder is a complex intellectual disorder.
Example
The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees celsius, and pressure is at or near atmospheric pressure. Standard abbreviations may be used, e.g., bp, base pairs; kb, kilobases; pl, picoliter; s or sec, seconds; min, min; h or hr, hr; aa, amino acids; kb, kilobases; bp, base pairs; nt, nucleotide; intramuscular injection; p. intraperitoneal injection; s.c., subcutaneous injection, etc.
Example 1: identification of Fem1b inhibitors
Chemical library composition
The U.S. Food and Drug Administration (FDA) -approved bioactive chemical library contains 1200 and 4170 small molecule compounds, respectively, stored at 10mM in 384 well plates (Targetmol, welsley mountain, ma) in dimethyl sulfoxide (DMSO) and 2mM screening master. A diverse library and an antimicrobial chemical library containing 100000 and 15000 small molecule compounds, respectively, were purchased from Chemdiv (san diego, california) and the storage conditions of both libraries were identical. Using a Cybio Well Vario liquid treatment workstation (Analytik Jena, yena, germany), 0.5. Mu.l of 2mM concentration screening master plates were spotted into non-binding surface 384 Well plates (Greiner, 781900), yielding a primary plate with a final concentration of 40. Mu.M and a DMSO concentration of 2%.
Hit points were selected from 10mM master plates and serially diluted using Tecan Freedom Evo 150 (Tecan Systems Inc, san jose, california).
Fluorescence polarization screening
For fluorescence polarization screening, mice MBP-FEM1B and mutants (e.g., R126A mutants of FEB 1B) were purified as described previously (Manford et al, (2020) cell 183:46), and TAMRA-labeled follicle stimulating hormone binding protein 1 (FNIP 1) polypeptide (5, 6-TAMRA-RNKSSLLFKESEETRTPNCNCKYCSHPVLG; SEQ ID NO: 3) was purchased from the Koch institute/Massa institute of technology biopolymer laboratory. The peptides were resuspended in DMSO to a concentration of 4mM and diluted with binding buffer (40 mM HEPES 7.5, 150mM NaCl, 0.2% NP40 substitute and 100. Mu.M TCEP (tris (2-carboxyethyl) phosphine hydrochloride) to a stock concentration of 200. Mu.M, and then aliquotted.
The plates were mixed using a QInstruments BioShake ELM3000 shaker (QInstruments, yena, germany) at 2400rpm for 45 seconds and after incubation for 60 minutes, the plates were measured on a 2104Envision plate reader (Perkin Elmer, waltherm, ma). Data (1000 x (S-G x P)/(s+g x P), s=595S channel 2, p=595P channel 1, g=1.1) were calculated from mP values and background differences were calculated from the control plate containing only polypeptides. Each assay group included peptide and DMSO only plates, as well as FEM1B-FNIP1 peptide DMSO only plates, in which the dose response containing TPEN (N, N' -tetrakis (2-pyridylmethyl) ethylenediamine, sigma-Aldrich, P4413) was used as a positive control (2-fold dilution, from 80 μm to about 156 nM). Data on each well plate was referenced to DMSO alone control.
FNIP1 degradation determinant reporter gene analysis
HEK293T cells were seeded into 6-well plates at a number of 30 ten thousand cells per well. The next day, cells were transfected in 300. Mu.l Opti-MEM (Thermo Fisher, 31985-070) (containing 12. Mu.g polyethylenimine (PEI, polysciences 23966-1)) using 60. Mu.l transfection mix consisting of 0.1. Mu.g FEM1B mitochondrial reporter (FNIP 1 (562-591) -GFP-GlySer48 linker-OMP 25 (110-145) -IRES-mCherry) and 1.9. Mu.g pCS2+. After 12 hours of transfection, 20. Mu.M of the indicated compound or DMSO was added. After 12 hours of treatment, cells were trypsinized, slowed, resuspended in dmem+10% Fetal Bovine Serum (FBS) and analyzed on Fortessa X20. Data processing was performed using FlowJo.
Primary screening results
Primary screeningThe results are shown in FIG. 1.
Secondary screening
The FNIP1 down-regulator stator was cloned in frame with mitochondrial targeting sequence and GFP and expressed with mCherry fluorescent protein ("mito reporter"). Both GFP and mCherry were assayed by Fluorescence Activated Cell Sorting (FACS). The secondary screening results are shown in FIGS. 2A-2O.
Degradation the ratio between stator-GFP and mCherry signals suggests that the stability of GFP fusion is dependent on FEM1B dependent degradation (degradation determinants have degraded if the distribution is at a lower GFP/mCherry ratio, i.e. shifted to the left in the figure, degradation determinants have stabilized if the ratio is higher, i.e. shifted to the right in the figure, as shown by the active compound).
Other Compounds
Other compounds identified in the screen are shown in figures 3 and 4.
Although the invention has been described with reference to specific embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to fall within the scope of the claims appended hereto.
Sequence listing
<110> board of university of california university board of directives
Rape, Michael
Schaletzky, Julia Sabine
Wehri, Eddie Eric
Manford, Andrew Garrett
<120> E3 ligase inhibitors and methods of use thereof
<130> BERK-447WO
<150> US 63/321,034
<151> 2022-03-17
<150> US 63/211,868
<151> 2021-06-17
<160> 3
<170> patent in version 3.5
<210> 1
<211> 627
<212> PRT
<213> Chile person
<400> 1
Met Glu Gly Leu Ala Gly Tyr Val Tyr Lys Ala Ala Ser Glu Gly Lys
1 5 10 15
Val Leu Thr Leu Ala Ala Leu Leu Leu Asn Arg Ser Glu Ser Asp Ile
20 25 30
Arg Tyr Leu Leu Gly Tyr Val Ser Gln Gln Gly Gly Gln Arg Ser Thr
35 40 45
Pro Leu Ile Ile Ala Ala Arg Asn Gly His Ala Lys Val Val Arg Leu
50 55 60
Leu Leu Glu His Tyr Arg Val Gln Thr Gln Gln Thr Gly Thr Val Arg
65 70 75 80
Phe Asp Gly Tyr Val Ile Asp Gly Ala Thr Ala Leu Trp Cys Ala Ala
85 90 95
Gly Ala Gly His Phe Glu Val Val Lys Leu Leu Val Ser His Gly Ala
100 105 110
Asn Val Asn His Thr Thr Val Thr Asn Ser Thr Pro Leu Arg Ala Ala
115 120 125
Cys Phe Asp Gly Arg Leu Asp Ile Val Lys Tyr Leu Val Glu Asn Asn
130 135 140
Ala Asn Ile Ser Ile Ala Asn Lys Tyr Asp Asn Thr Cys Leu Met Ile
145 150 155 160
Ala Ala Tyr Lys Gly His Thr Asp Val Val Arg Tyr Leu Leu Glu Gln
165 170 175
Arg Ala Asp Pro Asn Ala Lys Ala His Cys Gly Ala Thr Ala Leu His
180 185 190
Phe Ala Ala Glu Ala Gly His Ile Asp Ile Val Lys Glu Leu Ile Lys
195 200 205
Trp Arg Ala Ala Ile Val Val Asn Gly His Gly Met Thr Pro Leu Lys
210 215 220
Val Ala Ala Glu Ser Cys Lys Ala Asp Val Val Glu Leu Leu Leu Ser
225 230 235 240
His Ala Asp Cys Asp Arg Arg Ser Arg Ile Glu Ala Leu Glu Leu Leu
245 250 255
Gly Ala Ser Phe Ala Asn Asp Arg Glu Asn Tyr Asp Ile Ile Lys Thr
260 265 270
Tyr His Tyr Leu Tyr Leu Ala Met Leu Glu Arg Phe Gln Asp Gly Asp
275 280 285
Asn Ile Leu Glu Lys Glu Val Leu Pro Pro Ile His Ala Tyr Gly Asn
290 295 300
Arg Thr Glu Cys Arg Asn Pro Gln Glu Leu Glu Ser Ile Arg Gln Asp
305 310 315 320
Arg Asp Ala Leu His Met Glu Gly Leu Ile Val Arg Glu Arg Ile Leu
325 330 335
Gly Ala Asp Asn Ile Asp Val Ser His Pro Ile Ile Tyr Arg Gly Ala
340 345 350
Val Tyr Ala Asp Asn Met Glu Phe Glu Gln Cys Ile Lys Leu Trp Leu
355 360 365
His Ala Leu His Leu Arg Gln Lys Gly Asn Arg Asn Thr His Lys Asp
370 375 380
Leu Leu Arg Phe Ala Gln Val Phe Ser Gln Met Ile His Leu Asn Glu
385 390 395 400
Thr Val Lys Ala Pro Asp Ile Glu Cys Val Leu Arg Cys Ser Val Leu
405 410 415
Glu Ile Glu Gln Ser Met Asn Arg Val Lys Asn Ile Ser Asp Ala Asp
420 425 430
Val His Asn Ala Met Asp Asn Tyr Glu Cys Asn Leu Tyr Thr Phe Leu
435 440 445
Tyr Leu Val Cys Ile Ser Thr Lys Thr Gln Cys Ser Glu Glu Asp Gln
450 455 460
Cys Lys Ile Asn Lys Gln Ile Tyr Asn Leu Ile His Leu Asp Pro Arg
465 470 475 480
Thr Arg Glu Gly Phe Thr Leu Leu His Leu Ala Val Asn Ser Asn Thr
485 490 495
Pro Val Asp Asp Phe His Thr Asn Asp Val Cys Ser Phe Pro Asn Ala
500 505 510
Leu Val Thr Lys Leu Leu Leu Asp Cys Gly Ala Glu Val Asn Ala Val
515 520 525
Asp Asn Glu Gly Asn Ser Ala Leu His Ile Ile Val Gln Tyr Asn Arg
530 535 540
Pro Ile Ser Asp Phe Leu Thr Leu His Ser Ile Ile Ile Ser Leu Val
545 550 555 560
Glu Ala Gly Ala His Thr Asp Met Thr Asn Lys Gln Asn Lys Thr Pro
565 570 575
Leu Asp Lys Ser Thr Thr Gly Val Ser Glu Ile Leu Leu Lys Thr Gln
580 585 590
Met Lys Met Ser Leu Lys Cys Leu Ala Ala Arg Ala Val Arg Ala Asn
595 600 605
Asp Ile Asn Tyr Gln Asp Gln Ile Pro Arg Thr Leu Glu Glu Phe Val
610 615 620
Gly Phe His
625
<210> 2
<211> 627
<212> PRT
<213> mice
<400> 2
Met Glu Gly Leu Ala Gly Tyr Val Tyr Lys Ala Ala Ser Glu Gly Lys
1 5 10 15
Val Leu Thr Leu Ala Ala Leu Leu Leu Asn Arg Ser Glu Ser Asp Ile
20 25 30
Arg Tyr Leu Leu Gly Tyr Val Ser Gln Gln Gly Gly Gln Arg Ser Thr
35 40 45
Pro Leu Ile Ile Ala Ala Arg Asn Gly His Ala Lys Val Val Arg Leu
50 55 60
Leu Leu Glu His Tyr Arg Val Gln Thr Gln Gln Thr Gly Thr Val Arg
65 70 75 80
Phe Asp Gly Tyr Val Ile Asp Gly Ala Thr Ala Leu Trp Cys Ala Ala
85 90 95
Gly Ala Gly His Phe Glu Val Val Lys Leu Leu Val Ser His Gly Ala
100 105 110
Asn Val Asn His Thr Thr Val Thr Asn Ser Thr Pro Leu Arg Ala Ala
115 120 125
Cys Phe Asp Gly Arg Leu Asp Ile Val Lys Tyr Leu Val Glu Asn Asn
130 135 140
Ala Asn Ile Ser Ile Ala Asn Lys Tyr Asp Asn Thr Cys Leu Met Ile
145 150 155 160
Ala Ala Tyr Lys Gly His Thr Asp Val Val Arg Tyr Leu Leu Glu Gln
165 170 175
Arg Ala Asp Pro Asn Ala Lys Ala His Cys Gly Ala Thr Ala Leu His
180 185 190
Phe Ala Ala Glu Ala Gly His Ile Asp Ile Val Lys Glu Leu Ile Lys
195 200 205
Trp Arg Ala Ala Ile Val Val Asn Gly His Gly Met Thr Pro Leu Lys
210 215 220
Val Ala Ala Glu Ser Cys Lys Ala Asp Val Val Glu Leu Leu Leu Ser
225 230 235 240
His Ala Asp Cys Asp Arg Arg Ser Arg Ile Glu Ala Leu Glu Leu Leu
245 250 255
Gly Ala Ser Phe Ala Asn Asp Arg Glu Asn Tyr Asp Ile Met Lys Thr
260 265 270
Tyr His Tyr Leu Tyr Leu Ala Met Leu Glu Arg Phe Gln Asp Gly Asp
275 280 285
Asn Ile Leu Glu Lys Glu Val Leu Pro Pro Ile His Ala Tyr Gly Asn
290 295 300
Arg Thr Glu Cys Arg Asn Pro Gln Glu Leu Glu Ala Ile Arg Gln Asp
305 310 315 320
Arg Asp Ala Leu His Met Glu Gly Leu Ile Val Arg Glu Arg Ile Leu
325 330 335
Gly Ala Asp Asn Ile Asp Val Ser His Pro Ile Ile Tyr Arg Gly Ala
340 345 350
Val Tyr Ala Asp Asn Met Glu Phe Glu Gln Cys Ile Lys Leu Trp Leu
355 360 365
His Ala Leu His Leu Arg Gln Lys Gly Asn Arg Asn Thr His Lys Asp
370 375 380
Leu Leu Arg Phe Ala Gln Val Phe Ser Gln Met Ile His Leu Asn Glu
385 390 395 400
Ala Val Lys Ala Pro Asp Ile Glu Cys Val Leu Arg Cys Ser Val Leu
405 410 415
Glu Ile Glu Gln Ser Met Asn Arg Val Lys Asn Ile Ser Asp Ala Asp
420 425 430
Val His Ser Ala Met Asp Asn Tyr Glu Cys Asn Leu Tyr Thr Phe Leu
435 440 445
Tyr Leu Val Cys Ile Ser Thr Lys Thr Gln Cys Ser Glu Glu Asp Gln
450 455 460
Cys Arg Ile Asn Lys Gln Ile Tyr Asn Leu Ile His Leu Asp Pro Arg
465 470 475 480
Thr Arg Glu Gly Phe Ser Leu Leu His Leu Ala Val Asn Ser Asn Thr
485 490 495
Pro Val Asp Asp Phe His Thr Asn Asp Val Cys Ser Phe Pro Asn Ala
500 505 510
Leu Val Thr Lys Leu Leu Leu Asp Cys Gly Ala Glu Val Asn Ala Val
515 520 525
Asp Asn Glu Gly Asn Ser Ala Leu His Ile Ile Val Gln Tyr Asn Arg
530 535 540
Pro Ile Ser Asp Phe Leu Thr Leu His Ser Ile Ile Ile Ser Leu Val
545 550 555 560
Glu Ala Gly Ala His Thr Asp Met Thr Asn Lys Gln Asn Lys Thr Pro
565 570 575
Leu Asp Lys Ser Thr Thr Gly Val Ser Glu Ile Leu Leu Lys Thr Gln
580 585 590
Met Lys Met Ser Leu Lys Cys Leu Ala Ala Arg Ala Val Arg Ala Asn
595 600 605
Asp Ile Asn Tyr Gln Asp Gln Ile Pro Arg Thr Leu Glu Glu Phe Val
610 615 620
Gly Phe His
625
<210> 3
<211> 30
<212> PRT
<213> artificial sequence
<220>
<223> TAMRA-labeled follicle-stimulating hormone binding protein 1 (FNIP 1) polypeptide
<400> 3
Arg Asn Lys Ser Ser Leu Leu Phe Lys Glu Ser Glu Glu Thr Arg Thr
1 5 10 15
Pro Asn Cys Asn Cys Lys Tyr Cys Ser His Pro Val Leu Gly
20 25 30

Claims (74)

1. A composition comprising:
a1 A compound of formula (I):
wherein:
x is O, S or NH;
R 1 is aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl;
R 2 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, acyl, aminoacyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl;
R 3 、R 4 、R 5 、R 6 and R is 7 Each independently of the otherIs selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano, thiol;
b1 A pharmaceutically acceptable excipient; or (b)
a2 A compound as shown in any one of figures 1 to 4; and
b2 A pharmaceutically acceptable excipient.
2. The composition of claim 1, wherein R 1 Is thiophene or substituted thiophene.
3. The composition of claim 1, wherein R 1 Is phenyl or substituted phenyl.
4. A composition according to claim 3, wherein R 1 The method comprises the following steps:
wherein R is a Is hydrogen, hydroxy or halogen
Wherein,represents R 1 -a C bond.
5. The composition of claim 4 wherein R a Is hydrogen or halogen selected from fluorine, chlorine, bromine or iodine.
6. The composition of any one of claims 1-5, wherein R 2 Is alkyl, substituted alkyl, alkylaryl or substituted alkylaryl.
7. The composition of claim 6, wherein R 2 Is a C1-C8 straight chain or C1-C8 branched alkyl group.
8. The composition of claim 7, wherein R 2 Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, and octyl.
9. The composition of claim 6, wherein R 2 Is benzyl or substituted benzyl.
10. The composition of claim 9, wherein R 2 Is a halogen substituted benzyl group, wherein the halogen is selected from fluorine, chlorine, bromine or iodine.
11. The composition of any one of claims 1-5, wherein R 5 Is hydrogen or halogen selected from fluorine, chlorine, bromine or iodine.
12. A composition comprising:
a compound of formula (II):
wherein R is 1 Is aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl, and substituted heteroaralkyl; and
a pharmaceutically acceptable excipient.
13. The composition of claim 12, wherein R 1 Is phenyl or substituted phenyl.
14. The composition of claim 13, wherein R 1 Is a halogen substituted phenyl group, wherein the halogen is selected from fluorine, chlorine, bromine or iodine.
15. The composition of claim 12, wherein R 1 Is pyrazole or substituted pyrazole.
16. The composition of claim 15, wherein R 1 Is N-ethyl-3-methylpyrazole.
17. The composition of claim 15, wherein R 1 Is N-methyl-5-methylpyrazole.
18. The composition of claim 12, wherein R 1 Is pyridine.
19. The composition of claim 12, wherein R 1 Is thiophene.
20. A composition comprising:
a compound of formula (III):
wherein:
R 1 is alkyl, substituted alkyl, acyl alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R 2 、R 3 、R 4 、R 5 、R 6 and R is 7 Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano, and thiol; and
A pharmaceutically acceptable excipient.
21. The composition of claim 20, wherein R 7 Is hydrogen.
22. The composition of claim 20, wherein R 7 Is a nitro group.
23. The group of any one of claims 20-22A compound, wherein R 1 Is an acyl group.
24. The composition of any one of claims 23, wherein R 1 It is the result that the liquid crystal display device,
wherein R is a Is C1-C8 alkyl or substituted C1-C8 alkyl, and
wherein,represents R 1 -N bond.
25. The composition of claim 24, wherein R a Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.
26. The composition of claim 24, wherein R a Is C1-C8 alkyl substituted with aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
27. The composition of claim 26, wherein R a Is a C2 alkyl group substituted with a phenyl group.
28. The composition of any one of claims 20-27, wherein R 3 Is a hydroxyl group.
29. The composition of any one of claims 20-27, wherein R 3 Is an alkoxy group.
30. The composition of claim 26, wherein R 3 Is methoxy or ethoxy.
31. The composition of any one of claims 20-27, wherein R 3 Is a C1-C8 alkyl group.
32. The composition of claim 31, wherein R 3 Is methyl.
33. The composition of any one of claims 20-32, wherein R 4 Is a hydroxyl group.
34. The composition of any one of claims 20-32, wherein R 4 Is an alkoxy group.
35. The composition of claim 34, wherein R 4 Is methoxy or ethoxy.
36. The composition of any one of claims 20-32, wherein R 4 Is a C1-C8 alkyl group.
37. The composition of claim 26, wherein R 4 Is methyl.
38. The composition of any one of claims 20-37, wherein R 5 Is a hydroxyl group.
39. The composition of any one of claims 20-37, wherein R 5 Is an alkoxy group.
40. The composition of claim 39, wherein R is 5 Is methoxy or ethoxy.
41. The composition of any one of claims 20-37, wherein R 5 Is a C1-C8 alkyl group.
42. The set of claim 26A compound, wherein R 5 Is methyl.
43. A composition comprising:
a compound of formula (IV):
wherein:
R 1 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl;
R 2 、R 3 、R 4 、R 5 and R is 6 Each independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, halogen, nitro, amino, hydroxy, cyano, thiol, and colored alkoxide; and
a pharmaceutically acceptable excipient.
44. The composition of claim 43, wherein R is 1 Is thiophene.
45. The composition of claim 43, wherein R is 1 Is a substituted phenyl group.
46. The composition of claim 45, wherein R is 1 Is o-methoxyphenyl.
47. The composition of claim 45, wherein R is 1 The method comprises the following steps:
wherein,represents R 1 -C bond。
48. The composition according to claim 43, wherein:
R 2 is a hydroxyl group;
R 5 is bromine.
49. The composition of claim 43, wherein R is 2 Is methyl mercaptan.
50. The composition of any one of claims 1-49, wherein the pharmaceutically acceptable excipient is not dimethyl sulfoxide.
51. The composition of any one of claims 1-50, wherein the composition is a sterile composition.
52. A drug delivery device comprising the composition of any one of claims 1-51.
53. The drug delivery device of claim 52, wherein said device comprises a syringe containing said composition.
54. The drug delivery device of claim 52, wherein the device comprises a pump.
55. A method of inhibiting E3 ligase activity in a cell, the method comprising contacting the cell with a compound of formula I, II, III or IV or a compound as described in any one of figures 1-4.
56. The method of claim 55, wherein the E3 ligase is Fem1b.
57. The method of claim 55 or 56, wherein the cell is a cancer cell.
58. A method of treating cancer in a subject, the method comprising administering to the subject an effective amount of the composition of any one of claims 1-51.
59. The method of claim 58, wherein the cancer is lung adenocarcinoma.
60. The method of claim 58 or 59, further comprising administering to the individual at least one additional cancer chemotherapeutic agent or anti-cancer polypeptide.
61. The method of any one of claims 58-60, wherein the composition is administered orally, intraperitoneally, intramuscularly, or intravenously.
62. A method of treating a metabolic disorder in an individual, the method comprising administering to the individual an effective amount of the composition of any one of claims 1-51.
63. The method of claim 62, wherein the metabolic disorder is diabetes.
64. The method of claim 63, wherein the diabetes is type 2 diabetes.
65. The method of claim 62, wherein the metabolic disorder is non-alcoholic fatty liver disease (NAFLD).
66. The method of claim 65, wherein the NAFLD comprises non-alcoholic steatohepatitis (NASH).
67. The method of claim 65, wherein the NAFLD comprises liver steatosis.
68. The method of any one of claims 62-67, wherein the individual has a large body mass indexAt 30kg/m 2 。
69. The method of any one of claims 62-68, wherein the composition is administered orally, intraperitoneally, intramuscularly, or intravenously.
70. The method of any one of claims 62-69, further comprising administering to the individual at least one additional agent that treats the metabolic disorder.
71. The method of claim 70, wherein the at least one additional agent is selected from insulin, glucagon, statin, and thiazolidinedione.
72. A method of inhibiting proliferation of a cancer cell, the method comprising contacting the cell with a compound of formula I, II, III or IV or a compound as shown in any one of figures 1-4.
73. A method of treating a psychotic disorder in a subject, the method comprising administering to the subject an effective amount of the composition of any of claims 1-51.
74. The method of claim 73, wherein the mental disorder is a complex mental disorder.
CN202280055066.3A 2021-06-17 2022-06-16 E3 ligase inhibitors and methods of use thereof Pending CN117794533A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63/211,868 2021-06-17
US202263321034P 2022-03-17 2022-03-17
US63/321,034 2022-03-17
PCT/US2022/033793 WO2022266321A1 (en) 2021-06-17 2022-06-16 E3 ligase inhibitors and methods of use thereof

Publications (1)

Publication Number Publication Date
CN117794533A true CN117794533A (en) 2024-03-29

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Country Status (1)

Country Link
CN (1) CN117794533A (en)

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