Methods and compounds for restoring mutant p53 function

Inventors

Vu, Binh • Dominique, Romyr • Li, Hongju

Assignees

PMV Pharmaceuticals Inc

Abstract

Mutations in oncogenes and tumor suppressors contribute to the development and progression of cancer. The present disclosure describes compounds and methods to recover wild-type function to p53 mutants. 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.

Core Innovation

The invention provides compounds defined by a broad chemical formula scaffold in which Q1 is C1-alkylene or a bond, and multiple substituents R2, R3, R4, R13, R14, R15, R16, R17, R19, R20, R21, R22, R23, and R24 are independently selected from carbonyl, thio-, sulfonyl, amide, amine, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl groups, including substituted or unsubstituted forms, as well as hydrogen and halogen. The formula also allows R3 and R4 together with the nitrogen atom to form a substituted or unsubstituted ring, and includes pharmaceutically-acceptable salts. The disclosed scope is described as a broad structural class of compounds with extensive substituent variability.

The compounds are linked to p53 mutant biology and are described as binding a p53 mutant and increasing the ability of the p53 mutant to bind DNA. In the method context, a cell expressing the p53 mutant is contacted with a therapeutically-effective amount of the compound to induce apoptosis. The disclosure also ties the compounds to increasing the stability of a biologically-active conformation of a p53 mutant compared with the stability without the compound.

The invention further extends the same formula-defined compound class to treating cancer by administering a therapeutically-effective amount to a subject in need thereof. The documented content also includes specific example structures within the scaffold family, including indole-based compounds, piperidine, piperazine, morpholine, oxane, cyclohexyl, sulfonamide, sulfonyl, and 2,2,2-trifluoroethyl motifs, together with alkynyl linkers and substituted aryl or heteroaryl groups.

Claims Coverage

The patent contains three independent claims: one directed to a compound of a broad formula, one directed to inducing apoptosis by contacting p53 mutant-expressing cells with a compound that binds the p53 mutant and increases DNA binding, and one directed to treating cancer by administering the same compound class to a subject. Across the independent claims, the coverage centers on extensive substituent definitions, optional ring formation involving R3 and R4 with the nitrogen atom, and p53 mutant-related functional use.

Overall, the claims cover a broadly defined chemical scaffold with extensive substituent variability and optional ring formation, together with therapeutic methods based on binding p53 mutants, increasing mutant DNA binding, inducing apoptosis, and treating cancer.

Stated Advantages

Documented Applications