Methods and compounds for restoring mutant p53 function
Inventors
Vu, Binh • Dominique, Romyr • Li, Hongju • Fahr, Bruce • Chen, Yi
Assignees
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Publication Number
US-11926632-B2
Publication Date
2024-03-12
Expiration Date
Abstract
Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes compounds and methods that restore DNA binding affinity of p53 mutants. The compounds of the present disclosure can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA and activate downstream effectors involved in tumor suppression. The disclosed compounds can be used to reduce the progression of cancers that contain a p53 mutation.
Core Innovation
The patent describes a broad class of compounds defined by a general structural formula with multiple variable substituents X1, R1-R7, R8-R13, and R14-R19, together with optional pharmaceutically-acceptable salts. The structural definition permits alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups, with hydrogen and halogen options and heteroatom- and carbonyl-containing patterns such as C(O)NR8R9, NR8C(O)R9, OR10, SR11, C(O)R12, C(O)OR12, S(O)2R13, CN, and NHS(O)2R19. In some instances, substituents form rings with the carbon atoms to which they are bound, and the ring may be unsubstituted or substituted.
Within the variable framework, X1 is CR7 or N, R2 is OR10, and R3 is hydrogen, while R5a, R5b, and R5d are independently hydrogen or halogen. R1 is defined over a set including alkyl, NR8R9, C(O)NR8R9, NR8C(O)R9, OR10, SR11, C(O)R12, C(O)OR12, S(O)2R13, CN, hydrogen, or halogen, and R4 is alkyl, cycloalkyl, or straight or branched alkenyl, with alternatives including C(O)R13, C(O)OR13, S(O)2R13, or hydrogen. R6a through R6e are independently alkyl or cycloalkyl or one of NR14R15, OR16, SR17, C(O)NR14R15, NR14C(O)R15, CN, C(O)OR18, S(O)2R19, NHS(O)2R19, hydrogen, or halogen, and selected pairs among them can together form a ring.
The disclosure also includes structurally defined substituted heterocyclic and aromatic compounds, including quinoline, pyridine, pyrimidine, quinazoline, indazole, pyrazolo-fused, naphthalene, and pyrazolo[3,4-c]pyridine motifs. The described compounds include acrylamide, prop-2-enamido, propenamide, carboxamide, and related nitrile derivatives, with examples containing dimethylamino, methoxy, fluoro, chloro, trifluoromethyl, cyanoethyl, hydroxypropyl, piperidinyl, pyrrolidinyl, azabicyclo, and cyclohexyl substituents. The patent text focuses on defining and enumerating these structurally defined compounds and their pharmaceutically acceptable salt forms.
Claims Coverage
The claim coverage centers on one broad independent claim defining a compound by a detailed structural formula with extensive substituent variability and ring-forming options, together with pharmaceutically-acceptable salts. Dependent claims further narrow X1, R1, and R6 and specify NR3R4 embodiments, while preserving the overall genus.
Broad structural formula with variable substituents
A compound of formula wherein X1 is CR7 or N, and the remaining positions are defined by broad substituent classes including alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydrogen, halogen, and carbonyl- or heteroatom-containing patterns such as C(O)NR8R9, OR10, SR11, C(O)R12, C(O)OR12, S(O)2R13, CN, and related groups.
Ring-forming substitutions at R6 positions
Each of R6a, R6b, R6c, R6d, and R6e is independently selected from alkyl or cycloalkyl, or from heteroatom-containing and carbonyl-containing substituent forms, and pairs of R6 substituents can together form a ring with the carbon atoms to which they are bound.
Defined functional constraints at key positions
R2 is OR10, R3 is hydrogen, R4 is alkyl, cycloalkyl, or straight or branched alkenyl, and R5a, R5b, and R5d are each independently hydrogen or halogen.
Dependent claim narrowing of X1, R1, R6, and NR3R4
Dependent claims fix X1 as CR7 or N, restrict R1 to selected functional classes such as C(O)NR8R9, OR10, or CN, require that at least one R6 position bears C(O)NR14R15, NR14C(O)R15, or NR14R15, and include NR3R4 embodiments with fluorine or trifluoromethyl options.
Pharmaceutically-acceptable salts
The scope expressly includes pharmaceutically-acceptable salts of the compound.
The claims define a broad compound family by a detailed multi-variable scaffold, with explicit functional group constraints, ring-forming options at R6, and dependent claim refinements that narrow X1, R1, and R6 while preserving the overall genus. Pharmaceutically-acceptable salts are included.
Stated Advantages
Induces apoptosis.
Enhances mutant p53 DNA binding.
Enhances DNA binding for mutant p53 proteins versus wild-type p53, as stated in the provided summary context.
Restores mutant p53 function by increasing mutant p53 DNA-binding.
Provides downstream tumor-suppressive activity.
Induces apoptosis in p53-mutant cells.
Treats cancers with p53 mutations.
Documented Applications
Use in a pharmaceutical composition for cancer treatment.
Administration routes described include oral, intravenous, subcutaneous, and topical administration in the cancer treatment context.
Cancer types explicitly mentioned include ovarian cancer, breast cancer, lung cancer, and pancreatic cancer.
Inducing apoptosis in p53-mutant cells using the disclosed p53-binding compounds.
Treating cancers with p53 mutations using the disclosed p53-binding compounds, including via pharmaceutical compositions.
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