Methods and compounds for restoring mutant p53 function
Inventors
Vu, Binh • Dominique, Romyr • Li, Hongju • Fahr, Bruce • Good, Andrew
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11807644-B2
Publication Date
2023-11-07
Expiration Date
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 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.
Core Innovation
The invention provides compounds of a specified multi-substituent formula, together with pharmaceutically-acceptable salts thereof. The formula defines a substituted or unsubstituted ring A and multiple independently selectable substituent positions, including R1, R3, R4, R16 through R18, R19 through R20, R21 through R22, and R23 through R24, with broad classes such as alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, halogen, hydrogen, and specified carbonyl, thio, amino, oxo, and silane-related variants.
The disclosure includes embodiments in which R3 and R4 together with the nitrogen atom form a substituted or unsubstituted ring. Representative scaffolds include indole-, oxadiazole-, thiadiazole-, pyrazole-, thiophene-, thiazole-, pyrrole-, imidazole-, benzamide-, heteroaryl carboxamide-, and sulfonamide-containing derivatives, together with fluorinated motifs and fluorinated piperidine or related cyclic substituents.
The examples present substituted compounds and synthetic examples built on these scaffolds, including oxadiazole formation, amide bond formation, and late-stage functional-group interconversions. Representative compounds are presented with structural formulae, example compound names, and analytical characterization, including LC-MS and 1H NMR for intermediates and final compounds.
Claims Coverage
The independent claim is clm-00001 and broadly covers a compound of a specified multi-substituent formula, together with pharmaceutically-acceptable salts. The consolidated claim content centers on a single independent claim with multiple inventive selection points across ring A and the substituent sets R1, R3/R4, R16 through R18, R19 through R20, R21 through R22, and R23 through R24.
Multi-substituent compound formula with substituted or unsubstituted ring A
A compound of the formula wherein A is a substituted or unsubstituted ring, and multiple positions are defined by broad substituent classes including alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, heterocyclyl, halogen, hydrogen, and specified carbonyl, thio, amino, oxo, and silane-related options.
R3 and R4 ring-forming option
R3 and R4 are independently selected from broad substituent classes or may together with the nitrogen atom to which they are bound form a substituted or unsubstituted ring.
Pharmaceutically acceptable salts
The compound is expressly covered as a pharmaceutically-acceptable salt thereof.
Coverage is centered on a broad formula-based chemical genus with extensive substituent latitude at ring A and multiple R positions, optional ring formation through R3 and R4, and inclusion of pharmaceutically-acceptable salts.
Stated Advantages
Used for cancer treatment by slowing proliferation or killing cancer cells.
Provides multiple pharmaceutically-acceptable salt forms and includes stereoisomers and tautomers.
Stabilizes the folded conformation of mutant p53.
Increases DNA binding of mutant p53.
Activates downstream p53 effectors.
Induces apoptosis in p53-mutant cells.
Inhibits cancer progression.
Provides therapeutic treatment of cancer patients by administering therapeutically effective amounts.
Documented Applications
Cancer treatment by slowing proliferation or killing cancer cells, including use with pharmaceutical compositions and formulations such as liposomes.
Inducing apoptosis in cells expressing p53 mutants by contacting the cells with compounds that increase mutant DNA binding and/or stabilize active conformations of p53 mutants, including p53 Y220C.
Cancer treatment using therapeutically-effective amounts of the compounds for ovarian, breast, and lung cancer.
Administration by oral, IV, subcutaneous, and topical routes.
Treating cancer patients by administering therapeutically effective amounts of the described compounds.
Interested in licensing this patent?