Mutant p53 Compounds Restore DNA Binding via Intermediary Mediation

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Solution Overview

Problem

Cancer treatment is hindered by the inability to effectively restore wild-type function to mutant p53 proteins, which are prevalent in various cancers and disrupt DNA binding and tumor suppression mechanisms.

Innovation Solution

Development of compounds that selectively bind to mutant p53 proteins, enhancing their DNA binding ability and restoring wild-type function, thereby activating downstream tumor suppression pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If mutant p53 proteins are present in cancer cells, then tumor suppression function is lost, but the mutant p53 structure remains and can be targeted

Engineering Contradiction:

Improvetumor suppression functionVSAvoidp53 protein structure

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

Small molecule compounds act as intermediaries that bind to mutant p53 proteins and restore their DNA-binding function. The compounds serve as mediators between the mutant p53 and DNA, enabling the restoration of tumor suppression activity without requiring replacement of the mutant protein.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the functional parameters of mutant p53 by introducing small molecule binders that alter the protein's conformational state or binding affinity. This restores DNA-binding capability and tumor suppression function while maintaining the existing p53 protein structure.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If conventional cancer treatments are used, then some cancer cells are killed, but p53 mutant cells survive and continue to proliferate

Engineering Contradiction:

Improvecancer cell killing efficiencyVSAvoidtumor suppression restoration

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The invention converts the harmful presence of mutant p53 proteins into a beneficial therapeutic target. By specifically binding to and restoring mutant p53 function, the treatment transforms the previously harmful mutated proteins into functional tumor suppressors that can selectively kill cancer cells while sparing normal cells.

Inventive Principle:

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

3Reliability

If small molecule compounds are designed to bind mutant p53, then DNA binding ability is restored, but selective binding to mutant vs wild-type p53 must be maintained

Engineering Contradiction:

ImproveDNA binding abilityVSAvoidcompound structure design

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The small molecule compounds are designed to interact with specific local regions or conformational features of mutant p53 that differ from wild-type p53. This local targeting enables selective binding to mutant forms while restoring DNA-binding function, without requiring complex overall structural changes in the compound.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS11926632B2Methods and compounds for restoring mutant p53 function

Publication Date: 2024.03.12 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 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.