Macrocyclic Compounds for Allosteric Mutant KRAS Inhibition
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Solution Overview
Problem
Existing inhibitors have struggled to effectively target mutant KRAS proteins, particularly KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L, and G12C, due to the absence of druggable pockets on the protein surface, hindering the development of effective cancer treatments.
Innovation Solution
Development of macrocyclic compounds with specific structural features, including various heterocycloalkyl groups and functional substitutions, designed to inhibit mutant KRAS proteins by targeting allosteric sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional small-molecule inhibitors are used to target KRAS, then the molecular size is small and easy to administer, but the inhibitors cannot effectively bind to mutant KRAS proteins due to absence of druggable pockets
Solution Approach 1:
The patent changes the size parameter of the inhibitor molecule from small-molecule to macrocyclic compound. This parameter change enables the inhibitor to adopt complex three-dimensional conformations that can accommodate the allosteric binding site of mutant KRAS, thereby achieving effective binding despite the absence of traditional druggable pockets on the protein surface
2Reliability
If macrocyclic compounds with complex structures are developed to target allosteric sites, then inhibitor potency against mutant KRAS is improved, but synthesis difficulty and manufacturing complexity increase
Solution Approach 1:
The macrocyclic compound is designed with modular structural segments including heterocycloalkyl groups (B), linkers (L), and substitutable positions (R1, R2, R4, R5, R6). This segmentation allows the complex molecule to be constructed from standardized building blocks through sequential synthesis steps, making the manufacturing process more feasible despite the overall molecular complexity
Solution Approach 2:
The patent introduces specific functional groups and heteroatoms (O, S, N) at particular positions within the macrocyclic structure to create local binding interactions with the allosteric site. This local quality optimization ensures high potency at the binding interface while allowing other portions of the molecule to be synthesized using more straightforward chemistry
Data Source
AI summary
The present disclosure provides compounds useful for the inhibition of KRAS G12D, G12V, G12A, G12S, G13D, Q61H, Q61L or G12C. The compounds have a general Formula I′:wherein the variables of Formula I′ are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, cancer.