Methods and compounds for restoring mutant p53 function
Inventors
Vu, Binh • Dominique, Romyr • Li, Hongju • Fahr, Bruce • Good, Andrew
Assignees
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Publication Number
US-11814373-B2
Publication Date
2023-11-14
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 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 relates to a compound of a formula in which R1 is alkyl substituted with NR16R17, R2 is substituted alkyl, and R3 and R13 are hydrogen. R4 is aryl, heteroaryl, or heterocyclyl substituted with at least halo, and the compounds include pharmaceutically-acceptable salts.
R16 and R17 are each independently selected from —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 independently substituted or unsubstituted, or hydrogen or halogen. Each R21 and R22 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted, or hydrogen.
The disclosed embodiments include indole-based scaffolds with propargyl or prop-2-yn-1-yl linkers, 2,2,2-trifluoroethyl substitution, and substituted piperidine, piperazine, morpholine, pyrrolidine, oxane, azetidinyl, spiro, sulfonamide, benzamide, benzoate, urea, carboxamide, nitrile, ester, cyano, methanesulfonyl, ethanesulfonyl, and other related terminal groups. The examples also include stereochemical variants and multiple halogenated, fluoro-substituted, methoxy-substituted, and other substituted aryl, heteroaryl, or heterocyclyl groups within the disclosed scaffold.
Claims Coverage
The consolidated claim coverage centers on one independent compound formula with broad substituent definitions and pharmaceutically-acceptable salt coverage. The inventive features repeatedly present across the items are the R1/R2/R3/R4 framework, the defined options for R16/R17 and R21/R22, and dependent narrowing of R4 to fluoro-substituted heterocyclyl or aryl cases, piperidinyl substitution, and specific depicted structures.
General compound formula with defined substituent framework
A compound of the formula wherein R1 is alkyl substituted with NR16R17, R2 is substituted alkyl, and each of R3 and R13 is hydrogen, with R4 as aryl, heteroaryl, or heterocyclyl substituted with at least halo, and including pharmaceutically-acceptable salts.
Broad substituent definitions for R16 and R17
R16 and R17 are each independently selected from —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 independently substituted or unsubstituted, or hydrogen or halogen.
Independent definitions for R21 and R22
Each R21 and R22 is independently alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl, each independently substituted or unsubstituted, or hydrogen.
Fluoro-substituted heterocyclyl or aryl R4 refinements
Dependent claims narrow R4 to heterocyclyl substituted with at least fluoro and to aryl substituted with at least one fluoro group.
Piperidinyl R4 refinement
Dependent claims specify R4 substituted with piperidinyl.
Phenyl-defined R17 refinement
Dependent claims specify R17 as phenyl substituted with one of several specified functional groups, each independently substituted or unsubstituted.
Specific structure embodiments
Some claims define the compound as the specific chemical structure shown in the accompanying image(s).
Overall, the claims protect a broad formula-defined compound genus with fixed hydrogen at R3 and R13, an NR16R17-substituted alkyl at R1, a substituted alkyl at R2, and a halo-substituted aryl, heteroaryl, or heterocyclyl at R4. The dependent coverage further narrows R4 to fluoro-containing or piperidinyl embodiments, specifies phenyl-defined R17 variants, and includes specific depicted structures.
Stated Advantages
Oral bioavailability advantage.
Restores wild-type p53 function with respect to wild-type DNA-binding activity.
Induces apoptosis.
Supports cancer treatment.
Treating cancer by administering compounds that bind mutant p53.
Increasing DNA binding for p53 Y220C.
Potency stated as SC150 < 1 μM measured by HTRF for p53 Y220C.
Activates downstream tumor-suppression effectors.
Stabilizes p53 Y220C, described as a temperature-sensitive mutant, by compounds.
Induces p53 outputs, including apoptosis and other p53 outputs.
Documented Applications
Cancer treatment via administering Formula (I) compounds.
Cancer treatment based on compounds that bind p53 mutants, restore wild-type DNA-binding activity, and can induce apoptosis.
Treating cancer by administering compounds that bind mutant p53, including inducing apoptosis and increasing DNA binding for p53 Y220C.
Treating cancers with p53 mutations.
Inducing apoptosis and other p53 outputs via activation of downstream tumor-suppression effectors associated with p53.
An in vitro HT RF/TR-FRET DNA binding activity assay is described for stabilizing mutant p53 Y220C, reporting SC150 categories in Table 7.
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