Selective Binders That Reactivate Mutant p53 Tumor Suppression
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Solution Overview
Problem
Mutant p53 proteins, commonly found in cancer cells, lose their ability to bind DNA and activate downstream effectors due to structural mutations, leading to uncontrolled cell proliferation and cancer progression.
Innovation Solution
Development of compounds that selectively bind to mutant p53 proteins, stabilizing their structure and restoring their wild-type activity, including DNA binding function and activation of tumor suppression pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutant p53 protein is present in cancer cells, then tumor suppression function is lost, but the protein structure remains intact and can be targeted for restoration
Solution Approach 1:
The patent converts the harmful mutant p53 protein into a beneficial functional protein by using small molecules to restore its wild-type conformation and DNA-binding ability, thereby transforming the harmful mutation into a therapeutic opportunity
Solution Approach 2:
The patent changes the conformational parameters of the mutant p53 protein by introducing small molecule binders that stabilize the wild-type-like folded state, shifting the equilibrium from the mutant conformation back to the functional wild-type conformation
2Reliability
If small molecules are designed to bind mutant p53, then wild-type activity can be restored, but selective binding to mutant over wild-type p53 must be achieved
Solution Approach 1:
The patent applies local quality by designing small molecules that specifically target the unique structural features of mutant p53 (such as the hydrophobic cavity created by R273H mutation) while leaving wild-type p53 unaffected, achieving selective binding through localized molecular interactions
Solution Approach 2:
The small molecules act as intermediaries that mediate between the mutant p53 mutation and the functional restoration, binding to the mutant protein and inducing a conformational change that restores DNA-binding capability without directly modifying the mutation itself
3Productivity
If compounds are administered to restore p53 function, then cancer progression can be inhibited, but the compounds must reach sufficient concentrations in tumor cells
Solution Approach 1:
The patent employs self-service mechanisms where the mutant p53 protein itself serves as the target and delivery vehicle, with the small molecules selectively binding to and being retained by the mutant p53 within the cell, thereby achieving concentrated local effect at the site of action
Data Source
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.