Mutant p53 Molecular Chaperones for Restored DNA Binding

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Solution Overview

Problem

Cancer cells evade apoptosis through suppression of p53 function, leading to uncontrolled proliferation and metastasis, as p53 mutations destabilize the protein structure and impair its DNA-binding activity.

Innovation Solution

Development of compounds that bind to mutant p53 proteins, stabilizing the conformation and enhancing wild-type p53 activity, thereby restoring its DNA-binding ability and activating downstream tumor suppression pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If mutant p53 protein is present in cancer cells, then cell proliferation continues uncontrollably, but the protein structure becomes destabilized and loses DNA-binding activity

Engineering Contradiction:

Improvep53 DNA-binding activityVSAvoidp53 protein structure

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent employs small molecule compounds as intermediaries that bind to mutant p53 proteins and act as molecular chaperones, stabilizing the protein structure and enabling it to regain proper conformation and DNA-binding activity without directly modifying the p53 gene itself

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the physical-chemical parameters of the mutant p53 protein by introducing small molecule ligands that alter the protein's conformational equilibrium, shifting it from a destabilized state to a stabilized, functional state capable of DNA binding and tumor suppression

Inventive Principle:

Principle #35Parameter changes

2Productivity

If p53 function is suppressed in cancer cells, then uncontrolled proliferation occurs, but apoptosis pathways remain intact and could be activated

Engineering Contradiction:

Improveapoptosis activationVSAvoidp53 tumor suppression function

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies preliminary action by using small molecule compounds to pre-stabilize mutant p53 proteins before they can fully lose their function, preventing complete degradation of p53 activity and preparing the protein for subsequent DNA-binding and apoptosis activation events

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The invention converts the harmful presence of mutant p53 proteins (which normally lose function and promote cancer) into a beneficial therapeutic target by designing compounds that specifically bind to and reactivate these mutant proteins, turning the cancer-promoting mutation into a druggable target for apoptosis activation

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentEP4034104B1Methods and compounds for restoring mutant p53 function

Publication Date: 2025.08.06 PMV PHARMACEUTICALS INC

AI summary

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.