Isoindolinone Inhibitors Block MDM2-p53 Interaction
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Solution Overview
Problem
Current treatments for cancer, particularly those involving the TP53 gene, are limited by the inactivation of the p53 protein due to mutations or overexpression of MDM2, leading to uncontrolled tumour growth.
Innovation Solution
Development of novel isoindolin-1-one derivatives that selectively inhibit the MDM2-p53 interaction, thereby activating p53-mediated cell death in tumour cells while sparing normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cancer treatments targeting TP53 are used, then treatment coverage is provided, but effectiveness is reduced due to p53 inactivation by mutations or MDM2 overexpression
Solution Approach 1:
The patent introduces small molecule compounds as intermediary substances that bind to MDM2 and prevent its interaction with p53. These compounds act as mediators that disrupt the harmful MDM2-p53 binding, thereby restoring p53 function without directly modifying the mutated p53 gene or protein structure.
Solution Approach 2:
The invention changes the binding parameters of the MDM2-p53 interaction by introducing compounds that alter the affinity and specificity of this protein-protein interaction. By modifying the binding parameters through small molecule intervention, the system restores p53 activity despite the presence of MDM2 overexpression or mutation.
2Reliability
If MDM2-p53 interaction is inhibited to activate p53, then anticancer activity increases, but selectivity between tumour and normal cells must be maintained
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular features that target the unique structural characteristics of MDM2 in tumour cells. The compounds exploit local structural differences in the MDM2-p53 interaction interface to achieve selective inhibition in cancer cells while preserving normal cell function through differential expression or accessibility of the target site.
Data Source
AI summary
The invention provides a compound of formula (1).or tautomer or a solvate or a pharmaceutically acceptable salt thereof, wherein the various substituents are as defined in the claims.Also provided are pharmaceutical compositions containing the compounds of formula (I), processes for making the compounds and the medical uses of the compounds.