Tetrahydropyridopyrimidine Pan-KRAS Inhibitors for Broad Mutation Coverage
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Solution Overview
Problem
Current KRas inhibitors have not demonstrated sufficient safety and efficacy for treating KRas-mediated cancers, despite thirty years of research, highlighting the need for new pan-KRas inhibitors that can effectively target various KRas mutations.
Innovation Solution
Development of compounds represented by Formula (I) that inhibit KRas activity, including wild type and multiple mutated forms such as G12A, G12C, G12D, G12R, G12S, G12V, G13D, and Q61H, through specific structural modifications and pharmaceutical compositions for therapeutic use.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing KRas inhibitors are developed and tested, then KRas inhibition activity is achieved, but sufficient safety and efficacy for regulatory approval are not demonstrated
Solution Approach 1:
The patent applies parameter changes by developing new chemical compounds with modified molecular structures (Formula I) that exhibit improved KRas inhibition activity across multiple mutations. The structural modifications include varying substituents at positions A, B, Y1, and Y2 to optimize binding affinity and selectivity, thereby achieving both safety and efficacy requirements for regulatory approval
Solution Approach 2:
The patent implements universality by designing pan-KRas inhibitors that simultaneously target multiple KRas mutation types (G12C, G12D, G12V, G12A, G12S, G13D, Q61H, and wild-type KRas). This multi-functional approach allows a single compound to address diverse KRas-mediated cancers, improving both safety through broader efficacy and the likelihood of regulatory approval
2Measurement precision
If KRas inhibitors target specific mutations, then mutation-specific inhibition is achieved, but pan-KRas coverage across multiple mutations is insufficient
Solution Approach 1:
The patent achieves pan-KRas coverage through universality by designing compounds of Formula I that can bind to and inhibit multiple KRas mutation variants simultaneously. The molecular structure incorporates flexible substituents and core frameworks that accommodate variations in the KRas binding pocket across different mutations, enabling broad-spectrum inhibition while maintaining precision
Solution Approach 2:
The patent applies local quality by optimizing specific regions of the molecule (substituents at A, B, Y1, Y2 positions) to interact with local features of the KRas binding pocket that are conserved across mutations. This allows the compound to maintain precise inhibition of each mutation while achieving pan-KRas coverage through localized structural adaptations
Data Source
AI summary
The present invention relates to compounds that inhibit at least one of KRas wild type, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D and KRas Q61H, pharmaceutical compositions comprising the compounds and methods of use therefor.