KRAS G12D Inhibitors Targeting the GDP-Bound Pocket
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Solution Overview
Problem
The development of KRAS G12D inhibitors is challenging due to the lack of a clear binding pocket in the KRAS protein, necessitating the creation of safe and effective inhibitors to treat KRAS G12D-mediated cancers.
Innovation Solution
A series of compounds with specific structural features, including various substituents and functional groups, are designed to target the GDP-bound form of KRAS G12D, providing strong inhibitory effects on the protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If covalently bound inhibitors targeting mutated cysteine at codon 12 are developed, then inhibitory effect on KRAS G12C is improved, but applicability to other KRAS mutations (especially G12D) deteriorates
Solution Approach 1:
The patent develops a series of compounds with a common core structure (formula I) that can target multiple KRAS mutation types including G12C, G12D, G12V, G13D, and others. The compounds achieve this universality by binding to the GDP-bound form of KRAS at a previously unidentified pocket, rather than relying on mutation-specific cysteine residues. This allows a single compound class to function against diverse KRAS mutations while maintaining strong inhibitory effects.
2Reliability
If inhibitors are designed to target the GDP-bound form of KRAS, then binding affinity is improved, but selectivity against other RAS family members deteriorates
Solution Approach 1:
The patent exploits local structural differences in the GDP-bound form of KRAS compared to other RAS family members. By identifying and targeting a specific pocket unique to KRAS in its GDP-bound state, the compounds achieve both high binding affinity for KRAS and selectivity against HRAS and NRAS. The local structural features of the KRAS GDP-bound conformation are leveraged to create selective inhibition.
3Ease of manufacture
If a clear binding pocket is created through structural modification, then drugability is improved, but structural complexity of the protein target deteriorates
Solution Approach 1:
The patent extracts and utilizes a previously undiscovered pocket in the KRAS GDP-bound structure. Rather than attempting to create a binding pocket through protein engineering or structural modification, the invention identifies and targets an existing but previously unrecognized pocket that naturally forms in the GDP-bound state. This approach achieves drugability by leveraging the inherent structural features of KRAS without adding complexity to the target protein.
Data Source
AI summary
The present invention relates to KRAS G12D inhibitors and the uses thereof. In particular, the present invention relates to KRAS G12D inhibitors having structures shown as formula (I), a preparation method therefor, a pharmaceutical composition containing same, the use thereof as KRAS G12D inhibitors, and the use thereof in the treatment and/or prevention of cancers or tumors related to KRAS G12D, each substituent of formula (I) being as defined in the description.