Mutant p53-Binding Compounds for Restored DNA Binding
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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, leading to uncontrolled cell growth and cancer progression, as they are thermodynamically unstable and prone to denaturation.
Innovation Solution
Development of heterocyclyl compounds with halo substituents that selectively bind to mutant p53 proteins, stabilizing them and restoring their wild-type DNA-binding activity and transcriptional function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutant p53 proteins are used in cancer cells, then tumor suppression function is lost, but the proteins are thermodynamically unstable and prone to denaturation
Solution Approach 1:
The patent uses small molecule compounds as intermediaries that bind to mutant p53 proteins and stabilize their structure. These compounds act as molecular chaperones, preventing denaturation and enabling the mutant proteins to regain wild-type conformation and function, thereby restoring tumor suppression activity without requiring protein replacement
Solution Approach 2:
The patent applies parameter changes by modifying the thermodynamic stability of mutant p53 proteins through binding with stabilizing compounds. This shifts the equilibrium from denatured to folded states, changing the structural parameters of the protein to enable functional restoration and regain DNA-binding capability
2Productivity
If mutant p53 proteins are present in cancer cells, then uncontrolled cell growth occurs, but the proteins retain some structural integrity
Solution Approach 1:
The patent converts the harmful presence of mutant p53 proteins into a beneficial therapeutic opportunity. Instead of eliminating the mutant proteins, the approach uses stabilizing compounds to rescue their function, transforming the pathological state into a therapeutic benefit by restoring tumor suppression activity and inducing apoptosis in cancer cells
3Object-generated harmful factors
If wild-type p53 activity is restored in mutant proteins, then apoptosis induction increases, but the proteins require specific conformational changes
Solution Approach 1:
The patent applies preliminary action by using stabilizing compounds to pre-establish the correct conformational structure of mutant p53 proteins before they can exert their apoptotic function. The compounds bind in advance to prevent misfolding and ensure the proteins adopt the wild-type conformation necessary for DNA-binding and downstream apoptotic signaling
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds significantly enhance the DNA-binding ability and apoptotic potential of mutant p53, effectively inhibiting cancer progression by activating downstream targets and inducing apoptosis in cancer cells.
Implementation Method 1
a heterocyclyl group comprising a halo substituent, wherein the compound binds a mutant p53 protein and increases wild-type p53 activity of the mutant p53 protein
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.