Methods and compounds for restoring mutant p53 function
Inventors
Vu, Binh • Dominique, Romyr • Li, Hongju • Fahr, Bruce • Chen, Yi
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11731953-B2
Publication Date
2023-08-22
Expiration Date
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.
Core Innovation
The invention provides compounds of a specified formula built around isoindolinone, isoindole-1-oxo, benzo[e]isoindole, and related polycyclic scaffolds. The compounds include R1 defined as C(O)NH2 or CN, R2a and R2b as hydrogen, and broad substituent variability at R3 to R6 and R7 to R10, together with R13a and R17a where present. The allowed substituents include alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl groups, optionally substituted or unsubstituted, and pharmaceutically-acceptable salts are included.
The compound definitions further permit selected pairs of substituents to together form an unsubstituted or substituted ring, including R3 and R4, R4 and R5, R5 and R6, and in some content R3 and R6. The formulas also allow cyano, carbonyl-containing, heteroatom-containing, sulfonyl, sulfonamide-like, hydrogen, and halogen alternatives at specified positions, and in some claim language R17a is restricted to alkyl, aryl, or heteroaryl or to CN, NR7R8, S(O)2R7, SR7, OR7, hydrogen, or halogen. The examples present substituted isoindolinone, indazole, and related heteroaryl compounds, including prop-2-enenitrile and prop-2-enamide motifs.
The disclosed examples include indazole, pyridyl, thiazolyl, oxazolyl, benzodiazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, quinolinyl, pyrazolyl, pyrimidyl, thiophenyl, piperidine, piperazine, morpholine, oxetane, and oxirane variants. The examples also describe halogen, methoxy, methyl, methylthio, trifluoromethyl, amino, hydroxy, cyano, carbamoyl, amide, and sulfonamide substituents, together with reported analytical data such as molecular weights, LC-MS m/z values, yields, purities, and compound numbers.
Claims Coverage
The consolidated claim coverage centers on one broad independent compound claim with extensive substituent variation and inclusion of pharmaceutically-acceptable salts. Across the inputs, the recurring inventive features are the defined core formula, constrained R1 and R2a/R2b choices, broad substituent scope at R3 to R6 and R7 to R10, optional ring formation from selected pairs, and R13a/R17a definitions where present.
Specified compound formula with constrained R1
A compound of the formula wherein R1 is C(O)NH2 or CN, and in some claim language R13a is also C(O)NH2 or CN.
Fixed hydrogen at R2a and R2b
Each R2a and R2b is hydrogen.
Broad substituent variation at R3 to R6
Each of R3, R4, R5, and R6 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each substituted or unsubstituted, or selected from CN and multiple carbonyl, heteroatom, sulfonyl, hydrogen, or halogen options.
Broad substituent variation at R7 to R10 and R17a
Each of R7, R8, R9, and R10 is independently alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each substituted or unsubstituted, or hydrogen or halogen; R17a is alkyl, aryl, or heteroaryl, substituted or unsubstituted, or CN, NR7R8, S(O)2R7, SR7, OR7, hydrogen, or halogen.
Ring-forming substitution combinations
R3 and R4, R4 and R5, R5 and R6, and in some content R3 and R6, together with the attached carbon atoms, form an unsubstituted or substituted ring.
Pharmaceutically-acceptable salts
The compounds include pharmaceutically-acceptable salts thereof.
Overall, the claim coverage is a broad formula-defined compound class with constrained R1 and R2a/R2b, extensive substitution choices across multiple positions, optional ring formation from selected pairs, and explicit inclusion of pharmaceutically-acceptable salts.
Stated Advantages
Restoring mutant p53 function, including restored DNA-binding activity and downstream tumor-suppressive activity.
Selectivity versus wild-type p53.
Increased mutant p53 DNA-binding ability.
Enhanced p53 mutant DNA binding associated with stabilization of a biologically-active conformation relative to wild-type p53.
Inducing apoptosis.
Treating cancer.
Therapeutic use for treating cancers in subjects with p53 mutations is described.
Documented Applications
A method of inducing apoptosis by contacting cells with a therapeutically effective amount of a p53-mutant-binding compound.
A method of treating cancer in a subject by administering the p53-mutant-binding compound.
Inducing apoptosis and treating cancer by contacting cells expressing mutant p53 including R248Q/R248W and R273C/R273H.
Treating cancers in subjects with p53 mutations by inducing apoptosis, cell cycle arrest, or senescence, as described in the disclosure.
Treating cancer types explicitly mentioned: ovarian cancer, breast cancer, lung cancer, and pancreatic cancer.
Cancer contexts described include ovarian cancer, breast cancer, and lung cancer.
Interested in licensing this patent?