KRAS Small-Molecule Inhibitors for Multi-Mutant Cancer Targeting
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Solution Overview
Problem
Current KRAS-G12C inhibitors are limited in efficacy due to their targeting a fraction of KRAS mutations, and there is a need for effective inhibitors of KRAS-G12D and KRAS-G12V, as well as WT KRAS, to treat various cancers effectively.
Innovation Solution
Development of small molecule inhibitors, such as compounds of Formula (I), that modulate KRAS-G12C, KRAS-G12D, KRAS-G12V, and WT KRAS proteins, affecting the signaling pathway associated with cell growth and proliferation, thereby providing therapeutic benefits for oncological disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalent inhibitors targeting cysteine residue are used for KRAS-G12C, then inhibition efficacy for KRAS-G12C is improved, but applicability to other KRAS mutants (G12D, G12V) and WT KRAS deteriorates
Solution Approach 1:
The patent develops a small molecule inhibitor (Formula I) that functions as a universal inhibitor capable of binding to and inhibiting multiple KRAS mutant forms (G12C, G12D, G12V) and wild-type KRAS through a common mechanism, eliminating the need for mutant-specific inhibitors
2Reliability
If KRAS-G12C specific inhibitors are developed, then therapeutic benefit for LUAD patients is improved, but therapeutic coverage for other cancer types with different KRAS mutations deteriorates
Solution Approach 1:
The inhibitor of Formula I provides broad therapeutic coverage across multiple cancer types and KRAS mutation types by maintaining effective inhibition against G12C, G12D, G12V mutants and wild-type KRAS, enabling treatment of pancreatic ductal adenocarcinoma, colorectal cancers, lung adenocarcinoma and other KRAS-driven cancers
3Power
If covalent binding to cysteine is used as inhibition mechanism, then potency against KRAS-G12C is improved, but mechanism applicability to mutants without reactive cysteines (G12D, G12V) deteriorates
Solution Approach 1:
The patent changes the inhibition mechanism from covalent cysteine-specific binding to a non-covalent mechanism that recognizes conserved structural features of the KRAS switch II region, allowing the same molecular mechanism to effectively inhibit multiple mutant types and wild-type KRAS
Data Source
AI summary
Compounds of Formula (I) 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 Formula (I) 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.