Uses of p53 x-ray co-crystal structures
AssigneePmv Pharmaceuticals, Inc.
InventorsBinh Vu, Andrew Good
Life of this patent
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Abstract
Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. Disclosed herein are compounds and methods to recover wild-type function of p53 mutants using x-ray co-crystal structures of mutant p53 and compounds of the disclosure. The compounds of the present invention 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.
Claims8
A compound comprising a molecular structure that binds to a Y220C mutant p53 protein, wherein the Y220C mutant p53 protein has a mutant conformation, and the molecular structure modulates the mutant conformation of the Y220C mutant p53 protein into a conformation of p53 that possesses anti-cancer activity, wherein the molecular structure that binds to the Y220C mutant p53 protein comprises a hydrogen bond donor and a fluorine atom, wherein the hydrogen bond donor and the fluorine atom are substituents on a common ring, wherein the molecular structure is of the formula:
- wherein:
- each is independently a single bond or a double bond;
- X is CR5, CR5R6, N, NR5, O, S, C═O, C=S, or a carbon atom connected to Q1;
- X2 is CR7, CR7R8, N, NR7, O, S, C═O, C═S, or a carbon atom connected to Q1;
- X3 is CR9, CR9R10, N, NR9, O, S, C═O, C═S, or a carbon atom connected to Q1;
- X4 is CR11, CR11R12, N, NR11, O, S, C═O, C═S, or a carbon atom connected to Q1;
- X5 is CR13, N, or NR13;
- wherein at least one of X1, X2, X3, and X4 is a carbon atom connected to Q1;
- Q1 is a bond or C1-alkylene;
- m is 1;
- Y is N;
- ring A is 3-fluoro-1-methylpiperidinyl;
- R1 is —C(O)R16, —C(O)OR16, —C(O)NR16R17, —OR16, —SR16, —NR16R17, methyl substituted with NR16R17, —NR16C(O)R16, —OC(O)R16, —CN, —SiR16R17R18, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen;
- R3 is hydrogen;
- each R2, R5, R6, R7, R8, R9, R10, R11, R12, R13, R16, R17, and R18 is independently —C(O)R21, —C(O)OR21, —C(O)NR21R22, —OR21, —SR21, —NR21R22, —NR21C(O)R22, —OC(O)R21, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen or halogen;
- and
- each R21 and R22 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or
- heterocyclyl, each of which is independently substituted or unsubstituted, or hydrogen, wherein if a co-crystal is obtained of the compound and the Y220C mutant p53 protein with the compound bound to a binding site on the Y220C mutant p53 protein, and the co-crystal is obtained by sitting-drop vapor distillation, and if an x-ray co-crystal structure of the co-crystal is obtained by crystal soaking, and if the x-ray co-crystal structure has a resolution of about 2 Å, then in the x-ray co-crystal structure, the hydrogen bond donor forms a hydrogen bond with Thr-150 of the mutant p53 protein.
Dependencies are inferred from the claim text.