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US 2023/0056253 A1Published application
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
Estimating the term…
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.
Claims25
A compound of the formula:
- wherein:
- R1 is
- R13a is —C(O)NH2 or —CN;
- R17a is —CN, alkyl, aryl, heteroaryl, —NR7R8, —S(O)2R7, —SR7, or OR7, each which is unsubstituted or substituted, or hydrogen or halogen;
- each R2a, R2b, R3, R4, R5, and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —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, each which is independently substituted or unsubstituted, or hydrogen or halogen;
- or
- R2a and R2b together with the carbon atom to which R2a and R2b are bound is C═O or C═S;
- and R3, R4, R5, and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —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, each which is independently substituted or unsubstituted, or hydrogen or halogen;
- or
- R3 and R4 together with the carbon atom to which R3 and R4 are bound form a ring, wherein the ring is unsubstituted or substituted;
- and each R2a, R2b, R5 and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —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, each which is independently substituted or unsubstituted, or hydrogen or halogen;
- or
- R4 and R5 together with the carbon atom to which R4 and R5 are bound form a ring, wherein the ring is unsubstituted or substituted;
- and each R2a, R2b, R3, and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —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, each which is independently substituted or unsubstituted, or hydrogen or halogen;
- or
- R5 and R6 together with the carbon atom to which R5 and R6 are bound form a ring, wherein the ring is unsubstituted or substituted;
- and each R2a, R2b, R3, and R4 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —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, each which is independently substituted or unsubstituted, or hydrogen or halogen;
- and
- each R7, R8, R9, and R10 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each which is independently substituted or unsubstituted, or hydrogen or halogen,
- or a pharmaceutically-acceptable salt thereof.
17 more elements
24-25. (canceled)
Dependencies are inferred from the claim text.