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US 11,731,953 B2Granted
Methods and compounds for restoring mutant p53 function
AssigneePmv Pharmaceuticals, Inc.
InventorsBinh Vu, Romyr Dominique, Hongju Li, Bruce Fahr, Yi Chen
Life of this patent
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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.
Claims22
A compound of the formula:
- wherein:
- R1 is
- R13a is —C(O)NH2 or —CN;
- R17a is alkyl, aryl, or heteroaryl, each of which is unsubstituted or substituted, or —CN, —NR7R8, —S(O)2R7, —SR7, OR7, hydrogen, or halogen;
- and
- each R3, R4, R5, and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or —CN, —C(O)R9, —C(O)OR9, —C(O)NR9R10, —C(═N)NR9R10, —OR9, —SR9, —NR9R10, —NR9C(O)R10, —NR9C(O)OR10, —OC(O)R9, —OC(O)NR9R10, —S(O)2R9, —NHS(O)2R9, —OS(O)2R9, hydrogen, or halogen;
- or
- R3 and R4 together with the carbon atoms to which R3 and R4 are bound form a ring, wherein the ring is unsubstituted or substituted;
- and each R5 and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or —CN, —C(O)R9, —C(O)OR9, —C(O)NR9R10, —C(═N)NR9R10, —OR9, —SR9, —NR9R10, —NR9C(O)R10, —NR9C(O)OR10, —OC(O)R9, —OC(O)NR9R10, —S(O)2R9, —NHS(O)2R9, —OS(O)2R9, hydrogen, or halogen;
- or
- R4 and R5 together with the carbon atoms to which R4 and R5 are bound form a ring, wherein the ring is unsubstituted or substituted;
- and each R3 and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or —CN, —C(O)R9, —C(O)OR9, —C(O)NR9R10, —C(═N)NR9R10, —OR9, —SR9, —NR9R10, —NR9C(O)R10, —NR9C(O)OR10, —OC(O)R9, —OC(O)NR9R10, —S(O)2R9, —NHS(O)2R9, —OS(O)2R9, hydrogen, or halogen;
- or
- R5 and R6 together with the carbon atoms to which R5 and R6 are bound form a ring, wherein the ring is unsubstituted or substituted;
- and each R3 and R4 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or —CN, —C(O)R9, —C(O)OR9, —C(O)NR9R10, —C(═N)NR9R10, —OR9, —SR9, —NR9R10, —NR9C(O)R10, —NR9C(O)OR10, —OC(O)R9, —OC(O)NR9R10, —S(O)2R9, —NHS(O)2R9, —OS(O)2R9, hydrogen, or halogen;
- each R2a and R2b is hydrogen;
- and
- each R7, R8, R9, and R10 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen,
- or a pharmaceutically-acceptable salt thereof.
16 more elements
Dependencies are inferred from the claim text.