KRAS G12C Inhibitor Design via Segmentation and Local Quality
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Solution Overview
Problem
Current methods are inadequate for effectively targeting and inhibiting KRAS mutant proteins, particularly the G12C mutation, which is prevalent in various cancers, limiting therapeutic options for cancers such as lung, colon, and pancreatic cancer.
Innovation Solution
A compound of formula (I) and its stereoisomers, atropisomers, and pharmaceutically acceptable salts are developed, which can be used to inhibit KRAS mutant proteins, specifically the G12C mutation, through a coupling reaction between specific compounds, facilitating the treatment of related cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional small molecules are used to target KRAS G12C mutation, then the structural challenge of targeting the mutation is addressed, but the therapeutic effectiveness is insufficient
Solution Approach 1:
The compound is divided into distinct functional modules: a first substituent (R1-R6) that interacts with specific KRAS G12C residues, a core structure (formula II) that positions the molecule optimally, and a second substituent (R7-R12) that provides additional binding interactions. This segmentation allows each module to be optimized independently for its specific function, resolving the contradiction between targeting difficulty and therapeutic effectiveness.
Solution Approach 2:
The patent applies local quality by assigning specific chemical properties to different regions of the molecule. The first substituent is designed with specific steric and electronic properties to interact with residues near the mutation site, while the second substituent has different properties to interact with other regions of KRAS. This localized optimization of chemical properties enables effective targeting of the G12C mutation while maintaining overall therapeutic effectiveness.
2Adaptability or versatility
If small molecules are designed to specifically inhibit KRAS G12C, then mutation-specific targeting is achieved, but the complexity of molecule design increases
Solution Approach 1:
The core structure of formula (II) serves multiple functions simultaneously: it provides the structural framework for binding, positions both substituents optimally, and maintains appropriate rigidity and flexibility. This multi-functional core simplifies the overall design by eliminating the need for separate structural elements, thereby achieving mutation-specific targeting without excessive molecular complexity.
Solution Approach 2:
The patent performs preliminary action by pre-optimizing the core structure (formula II) with specific structural features before attaching the substituents. The core is designed in advance with predetermined geometric and electronic properties that facilitate subsequent substitution and ensure optimal binding to KRAS G12C. This preliminary structuring reduces the complexity of final molecule design while maintaining high adaptability for specific mutation targeting.
Data Source
AI summary
The invention relates to a KRAS mutant protein inhibitor shown as formula (I), a composition containing the inhibitor and the use thereof.