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US 11,926,632 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
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.
Claims12
A compound of formula:
- wherein:
- X1 is CR7 or N;
- R1 is alkyl that is unsubstituted or substituted, or —NR8R9, —C(O)NR8R9, —NR8C(O)R9, —OR10, —SR11, —C(O)R12, —C(O)OR12, —S(O)2R13, —CN, hydrogen, or halogen;
- R2 is —OR10;
- R3 is hydrogen;
- R4 is alkyl, cycloalkyl, or straight or branched alkenyl, each of which is unsubstituted or substituted, or —C(O)R13, —C(O)OR13, —S(O)2R13, or hydrogen;
- R5a, R5b, and R5d are each independently hydrogen or halogen;
- each of R6a, R6b, R6c, R6d, and R6e is independently alkyl or cycloalkyl, each of which is unsubstituted or substituted, or —NR14R15, —OR16, —SR17, —C(O)NR14R15, —NR14C(O)R15, —CN, —C(O)OR18, —S(O)2R19, —NHS(O)2R19, hydrogen, or halogen;
- or R6a and R6b together with the carbon atoms to which R6a and R6b are bound form a ring, wherein the ring is unsubstituted or substituted, and each of R6c, R6d, and R6e is independently alkyl or cycloalkyl, each of which is unsubstituted or substituted, or —NR14R15, —OR16, —SR17, —C(O)NR14R15, —NR14C(O)R15, —CN, —C(O)OR18, —S(O)R19, —NHS(O)2R19, hydrogen, or halogen;
- or —R6b and R6c together with the carbon atoms to which R6b and R6c are bound form a ring, wherein the ring is unsubstituted or substituted, and each of Ra R66, and R6e is independently alkyl or cycloalkyl, each of which is unsubstituted or substituted, or —NR14R15, —OR16, —SR17, —C(O)NR14R15, —NR14C(O)R15, —CN, —C(O)OR18, —S(O)2R19, —NHS(O)2R19, hydrogen, or halogen:
- or R6c and R6d together with the carbon atoms to which R6c and R6d are bound form a ring, wherein the ring is unsubstituted or substituted, and each of R6a, R6b, and R6c is independently alkyl or cycloalkyl, each of which is unsubstituted or substituted, or —NR14R5, —OR16, —SR17, —C(O)NR14R15, —NR14C(O)R15, —CN, —C(O)OR18, —S(O)2R19, —NHS(O)2R19, hydrogen, or halogen;
- or R6d and R6e together with the carbon atoms to which R6d and R6e are bound form a ring, wherein the ring is unsubstituted or substituted, and each of R6a, R6b, and R6c is independently alkyl or cycloalkyl, each of which is unsubstituted or substituted, or —NR14R15, —OR16, —SR17, —C(O)NR14R15, —NR14C(O)R15, —CN, —C(O)OR18, —S(O)2R19, —NHS(O)2R19, hydrogen, or halogen;
- R7 is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen or halogen;
- each of R8 and R9 is alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen;
- or R8 and R9 together with the atom(s) to which R8 and R9 are bound form a ring, wherein the ring is unsubstituted or substituted;
- each of R10, R11, R12, and R13 is independently alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen or halogen;
- each of R14 and R15 is independently alkyl, alkenyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is unsubstituted or substituted, or hydrogen;
- and
- each of R16, R17, R18, and R19 is independently alkyl, alkenyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is unsubstituted or substituted, or hydrogen or halogen,
- or a pharmaceutically-acceptable salt thereof.
17 more elements
Dependencies are inferred from the claim text.