Methods and compounds for restoring mutant p53 function
Inventors
Vu, Binh • Dominique, Romyr • Li, Hongju
Assignees
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Publication Number
US-10640485-B2
Publication Date
2020-05-05
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 disclosure provides compounds defined by a structural formula in which a variable linker Q1 and multiple substituent positions are independently selected from broad classes of hydrocarbon, heteroaryl, and heterocyclyl fragments with extensive functional-group substitution. The structural scope includes options where Q1 is selected from C=O, C=S, C=CR14R15, C=NR14, alkylene, alkenylene, alkynylene, or a bond, and where R1 and related positions can be carbonyl, ester, ether, thio, amino, nitrile, silyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl fragments.
A key structural feature is that R3 and R4 are independently selected substituents or may together with the nitrogen atom to which they are bound form a ring that is unsubstituted or substituted with the listed functional groups. The compounds further include pharmaceutically-acceptable salts, and the examples describe indole-based substituted compounds, including trifluoroethyl-substituted indole cores, propargyl or alkynyl linkers, and substituted anilide, sulfonamide, pyridine, and heterocyclic substituents.
The examples also present variations in side-chain and terminal substituents, including piperidine, piperazine, morpholine, pyrrolidine, oxane, azetidine, cyclohexylamine, and other heterocycle-containing motifs. Reported example data include LC-MS [M+H]+ values and structure images, and the disclosure repeatedly presents the compounds as members of a common scaffold with broad substituent flexibility.
Claims Coverage
The provided record centers on independent claim 1, which defines a broad structural genus with a variable linker Q1 and multiple independently selected substituent positions. The inventive coverage is expressed through the breadth of the substituent definitions, the optional ring formation involving R3 and R4 with the attached nitrogen atom, and the inclusion of pharmaceutically-acceptable salts. One independent claim is explicitly identified in the supplied material.
Variable linker Q1 in the compound formula
A compound of the formula wherein Q1 is selected from C=O, C=S, C=CR14R15, C=NR14, alkylene, alkenylene, alkynylene, or a bond, with each option independently unsubstituted or substituted with the listed functional groups.
Broad substituent definitions at R1 and related positions
R1 is selected from carbonyl, ester, ether, thio, amino, nitrile, silyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclyl groups, each independently unsubstituted or substituted with the listed functional groups, or hydrogen; similar broad substitution is provided for the other defined R positions.
R3 and R4 ring formation with the attached nitrogen
R3 and R4 are independently selected from broad substituent classes or hydrogen, and R3 and R4 together with the nitrogen atom to which they are bound may form a ring that is unsubstituted or substituted with the listed functional groups; alternatively, R3 is absent.
Pharmaceutically-acceptable salts
The compound includes a pharmaceutically-acceptable salt thereof.
Claim coverage is centered on a formula-defined compound class with broad and independently variable substituent positions, optional ring formation involving R3 and R4 with the attached nitrogen, and express coverage of pharmaceutically-acceptable salts.
Stated Advantages
Increases p53 Y220C DNA binding activity with sequence specificity versus a random DNA control.
Restoring wild-type function to mutant p53.
Increasing p53 mutant activity.
Restoring DNA-binding ability.
Inducing downstream tumor-suppressive signaling, including apoptosis.
Can be used to treat cancer by slowing proliferation or killing cancer cells.
May show non-lethal toxicity.
Documented Applications
In vitro HTRF/FRET DNA-binding activity assay for p53 Y220C using His-tagged p53 truncation 94–312 and biotin-labeled consensus DNA sequence SEQ ID NO:2 with APC anti-His acceptor and europium-streptavidin donor.
Methods of increasing p53 mutant activity by contacting a cell with a compound that binds mutant p53, restoring DNA-binding ability and inducing downstream tumor-suppressive signaling including apoptosis.
Treatment of cancers harboring p53 mutations.
Treatment of cancer, including slowing proliferation or killing cancer cells.
Therapeutic methods directed to cancer indications including ovarian, breast, and lung.
Use of FRET-based DNA-binding activation assays with tagged mutant p53 to evaluate functional activation and compare SC150 values versus controls in a testing context involving a p53 Y220C mutant truncation sequence.
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