Small-Molecule KRAS Inhibitors for Multi-Mutation Targeting
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Solution Overview
Problem
Current KRAS inhibitors primarily target the KRAS-G12C mutation, which accounts for only a fraction of KRAS mutations, while other prevalent mutations like KRAS-G12D and KRAS-G12V lack reactive cysteines in their active site, and WT KRAS amplification occurs in certain cancers, necessitating new approaches for effective inhibition.
Innovation Solution
Development of small molecule inhibitors, such as compounds of Formulae (I)-(VII), that selectively target KRAS-G12C, KRAS-G12D, KRAS-G12V, KRAS-G13D, and WT KRAS proteins, modulating their activity to affect signaling pathways associated with oncological disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalent inhibitors targeting cysteine residue are used to inhibit KRAS-G12C, then inhibition efficacy for KRAS-G12C is improved, but applicability to other KRAS mutations (G12D, G12V) and WT KRAS is limited
Solution Approach 1:
The patent develops a series of small molecule inhibitors (Formulae I-VII) that are designed to function across multiple KRAS mutation types (G12C, G12D, G12V) and wild-type KRAS, transforming a mutation-specific inhibitor into a universal KRAS inhibitor platform through systematic structural optimization and diversification
2Measurement precision
If inhibitors are designed to target specific mutation types, then selectivity for that mutation is improved, but coverage of other prevalent mutations is reduced
Solution Approach 1:
The patent employs systematic modification of molecular parameters including substituent groups (R1-R6), core structures, and chemical properties to create a library of inhibitors with optimized binding characteristics for different KRAS mutation types, enabling broad-spectrum coverage while maintaining mutation-specific selectivity through structure-activity relationship optimization
Data Source
AI summary
Compounds of Formulae (I)-(VII) or their pharmaceutically acceptable salts can inhibit the G12C, G12D, G12V, and/or G13D mutants of Kirsten rat sarcoma (KRAS) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The disclosure also provides pharmaceutical compositions which comprise compounds of Formulae (I)-(VII) or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.