RAS Inhibitor Compounds for Multi-Mutation Effector Disruption
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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 addressing secondary resistance to standard therapies with limited toxicity.
Innovation Solution
The use of compounds of formula (I) that inhibit RAS protein activation by disrupting the interaction between RAS and its effectors, specifically targeting KRAS, HRAS, and NRAS, regardless of their mutational status, thereby uncoupling the active RAS-effector interaction in a GTP-dependent manner.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If KRAS G12C specific inhibitors are used, then cancer treatment efficacy is improved for G12C mutants, but resistance develops in patients with other RAS mutations or secondary mutations
Solution Approach 1:
The patent applies universality by developing a compound that can inhibit multiple RAS isoforms (KRAS, HRAS, NRAS) and multiple mutation types (G12C, G12V, G13D, etc.) through a single mechanism of action targeting the RAS effector interaction interface, making the treatment applicable to diverse RAS mutation profiles including those resistant to mutation-specific inhibitors
Solution Approach 2:
The patent uses an intermediary mechanism by targeting the RAS-effector interaction interface rather than directly binding to the RAS mutation site. This indirect approach disrupts the functional output of RAS activation by preventing effector binding, thereby overcoming resistance mechanisms that arise from direct mutation-specific targeting
2Reliability
If RAS effector interaction is disrupted, then RAS oncogene activation is inhibited, but the mechanism is complex and requires precise GTP-dependent uncoupling
Solution Approach 1:
The patent extracts the critical functional output of RAS activation by targeting specifically the effector interaction interface. Instead of attempting to inhibit all RAS functions broadly, the compound selectively disrupts the RAS-effector binding interaction, which is the downstream functional consequence of RAS activation, thereby achieving reliable inhibition through a focused mechanism
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. 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).