Tetrahydropyridopyrimidine Pan-KRas Inhibitors for Multi-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 multiple KRas mutations.
Innovation Solution
Development of compounds of Formula (I) and their pharmaceutically acceptable salts, which inhibit KRas activity, including wild type and specific mutations such as G12A, G12C, G12D, G12R, G12S, G12V, G13D, and Q61H, through various substituents and functional groups, capable of modulating KRas enzymatic activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If compounds are designed to target multiple KRas mutations (pan-KRas inhibition), then the coverage and versatility of treatment is improved, but the complexity of achieving sufficient efficacy across all mutations increases
Solution Approach 1:
The patent applies universality by designing a single compound (Formula I) that functions against multiple KRas mutation types (G12C, G12D, G12V, G13D, Q61H, and wild-type KRas). The compound achieves this through a versatile binding mechanism that targets the nucleotide-binding pocket, allowing it to inhibit GDP-bound, GTP-bound, and transition-state KRas forms simultaneously, thereby providing broad-spectrum pan-KRas inhibition with one agent.
Solution Approach 2:
The patent employs parameter changes by optimizing specific molecular parameters of the compound including the substituent patterns on the aryl/heteroaryl ring (R1-R4 groups), the heterocyclic ring structure, and the linker region to achieve optimal binding affinity across diverse KRas mutations. By systematically varying these chemical parameters, the compound maintains effective inhibition across multiple mutation types while managing the complexity through structured molecular design.
2Reliability
If thirty years of discovery efforts have been invested in KRas inhibitors, then the knowledge base and research depth are improved, but the lack of approved therapies indicates insufficient efficacy and safety have been achieved
Solution Approach 1:
The patent applies preliminary action by conducting extensive in silico screening and in vitro validation against multiple KRas mutation types before clinical development. The compound undergoes comprehensive characterization including binding affinity measurements, cellular activity assays, and selectivity profiling across different KRas variants, ensuring that efficacy and safety concerns are addressed in advance of clinical trials, thereby reducing the risk of late-stage failures.
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.