Pan-RAS Inhibitors That Uncouple GTP-Dependent Effector Binding
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Solution Overview
Problem
Current treatments for RAS-related disorders, particularly those involving KRAS, HRAS, and NRAS mutations, face challenges in effectively inhibiting RAS oncogene activation and combating secondary resistance to standard therapies with limited toxicity and specificity.
Innovation Solution
Compounds of formula (I), particularly (A) and (B), inhibit RAS oncogene activation by uncoupling the active RAS-effector interaction in a GTP-dependent manner, effectively targeting KRAS, HRAS, and NRAS irrespective of their mutational status.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutation-specific KRAS inhibitors are used, then inhibition of KRASG12C is improved, but resistance develops and secondary mutations in other RAS isoforms occur
Solution Approach 1:
The compound is designed to inhibit all three RAS isoforms (KRAS, HRAS, and NRAS) simultaneously, rather than targeting only KRASG12C. This multi-functional approach prevents resistance development by blocking alternative pathways that would otherwise be available to mutated RAS proteins.
Solution Approach 2:
Instead of trying to overcome resistance to mutation-specific inhibitors, the invention inverts the approach by using a pan-RAS inhibitor that prevents resistance from developing in the first place. The compound targets the common mechanism of RAS activation across all isoforms rather than attempting to address each mutation individually.
2Adaptability or versatility
If pan-RAS inhibition is achieved, then coverage of all RAS isoforms is improved, but specificity and selectivity become challenging
Solution Approach 1:
The compound exhibits different binding characteristics for different RAS isoforms while maintaining overall pan-inhibition. The molecular structure is designed to interact with specific regions of the RAS proteins that are conserved across isoforms, allowing selective targeting of the RAS family while sparing other GTPases.
Solution Approach 2:
The compound achieves pan-RAS inhibition through specific physicochemical parameters including molecular weight, hydrophobicity, and binding affinity. These parameters are optimized to ensure the compound can bind to all three RAS isoforms with appropriate selectivity while maintaining drug-like properties.
3Reliability
If RAS effector interaction is uncoupled in a GTP-dependent manner, then RAS activation inhibition is improved, but complexity of the inhibition mechanism increases
Solution Approach 1:
The compound acts as an intermediary that binds to the RAS-GTP complex and prevents effector protein interaction. Rather than directly hydrolyzing GTP or altering RAS structure, the compound mediates inhibition by blocking the interface between RAS and its effectors, simplifying the mechanism while maintaining GTP-dependence.
Data Source
AI summary
The present invention relates to the use of compounds of formula (I) as RAS inhibitors and as a medicament, in particular for use in treating proliferative disorders, inflammatory diseases and/or genetic disorders and/or genetic disorders. The present invention relates further to a pharmaceutical composition comprising the compounds of formula (I). Moreover, the present invention relates to a method of inhibiting growth, proliferation or metastasis of cancer cells in a subject in need thereof, in particular which may encompass subsets of patients defined by their mutational status of the RAS oncogene or patients who might have developed resistance to the standard of care or treatment with RAS mutation specific inhibitors. The present invention also relates to a method of inhibiting RAS molecules in treating genetic disorders like RASopathies or inflammatory disorders like Adenomyosis where KRAS gene is mutationally activated. In addition, the present invention relates to a method of inhibiting proliferation and/or secretion of factors from a cell population sensitive towards inhibiting RAS activation in vitro, in particular sensitive towards inhibiting KRAS, HRAS and NRAS activation in vitro. Furthermore, the present invention relates to a kit containing a formulation comprising a pharmaceutical composition comprising a compound of formula (I).