Macrocyclic KRAS Inhibitors for Allosteric Mutant Binding
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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 proteins, then the molecular size is small and easy to administer, but they 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 (traditional) to large (macrocyclic, 80-200 Da to 400-800 Da molecular weight). This parameter change enables the inhibitor to occupy the allosteric pocket and form sufficient interactions with mutant KRAS proteins (G12C, G12D, G12V, G12A, G12S, G13D, Q61H, Q61L), thereby achieving effective binding despite the increased molecular complexity
Solution Approach 2:
The patent transitions from traditional linear/small molecule inhibitors to macrocyclic structures with cyclic architectures containing 8-20 atoms in the ring. This dimensional/structural change creates a three-dimensional binding pocket that can accommodate the allosteric site of mutant KRAS proteins, enabling effective inhibition through a different structural paradigm
2Reliability
If macrocyclic compounds with complex structures are developed to target allosteric sites, then binding efficacy to mutant KRAS improves, but synthesis difficulty and manufacturing complexity increase
Solution Approach 1:
The macrocyclic compounds are designed with modular building blocks including heterocycloalkyl groups (B), linkers (L), and substitutable positions (R1, R2, R4, Rx). This segmentation allows the complex macrocyclic structure to be constructed from smaller, more manageable fragments through stepwise synthesis, improving manufacturing feasibility while maintaining the three-dimensional allosteric binding capability
Solution Approach 2:
The patent introduces variable substituents (R1, R2, R4, Rx) at specific positions on the macrocyclic structure, allowing local optimization of binding interactions with different mutant KRAS variants. This local quality adjustment enables a single macrocyclic scaffold to achieve broad-spectrum inhibition across multiple mutants (G12C, G12D, G12V, G12A, G12S, G13D, Q61H, Q61L) without requiring complete structural redesign for each variant
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.