Mutant RAS Modulators for Blocking GDP-GTP Exchange
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Solution Overview
Problem
Mutations in the RAS genes, particularly in kRAS, are prevalent in various human tumors, leading to prolonged activation of the RAS protein and uncontrolled cell proliferation, which can result in cancer. Current compounds targeting RAS activity have limited efficacy against kRAS mutations, necessitating the development of more effective modulators.
Innovation Solution
Development of specific compounds that modulate the activity of mutant RAS proteins, particularly kRAS, by inhibiting the exchange of GDP for GTP, thereby preventing activation of downstream targets and inhibiting RAS-induced cell growth and proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current compounds targeting RAS activity are used, then some RAS inhibition is achieved, but efficacy against kRAS mutations is limited
Solution Approach 1:
The patent develops compounds with specific structural features (such as the RAS-binding domain interactions) that are optimized to recognize and bind to mutant RAS proteins, particularly kRAS G12C and other oncogenic mutations. This local optimization of binding affinity and selectivity for mutant forms while maintaining broader RAS coverage represents the local quality principle.
Solution Approach 2:
The invention involves modifying chemical parameters of RAS-targeting compounds, including molecular weight, hydrophobicity, and functional group composition, to enhance both mutation-specific efficacy and broad RAS inhibition. The systematic variation of compound parameters to achieve optimal balance between selectivity and versatility applies the parameter changes principle.
2Reliability
If compounds inhibit GDP-GTP exchange to prevent RAS activation, then downstream target activation is blocked, but achieving sufficient inhibition potency is challenging
Solution Approach 1:
The patent describes compounds that can be viewed as segmented structures with specific functional domains: a core scaffold that binds to the RAS switch region and additional substituents that enhance binding affinity and selectivity. This segmentation of the molecule into functional modules allows optimization of potency without excessive overall complexity.
Solution Approach 2:
The compounds act as intermediary molecules that facilitate the inhibition of GDP-GTP exchange by binding to the RAS protein and stabilizing the GDP-bound state. The chemical structure serves as an intermediary that translates the inhibition mechanism into effective biological activity, bridging the gap between molecular interaction and functional outcome.
Data Source
AI summary
RAS modulating compounds and methods of using the same are provided. The compounds find use in modulating the activity of a target RAS in a sample. The target RAS can be a mutant RAS that is implicated in a disease of interest. In some cases, the subject compounds can inhibit the growth of cancer cells whose progression is driven by kRAS or a mutated kRAS. Methods of treating a subject for a RAS driven disease including administering a therapeutically effective amount of the subject compound are provided. Also provided are pharmaceutical compositions and kits which include the subject compounds.