RAS Inhibitor Compounds That Disrupt RAS-Effector Coupling
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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 resistance to standard therapies with limited toxicity and specificity.
Innovation Solution
The use of compounds of formula (I), such as tegaserod and its derivatives, functions as RAS inhibitors by uncoupling active RAS from its effectors at the plasma membrane, disrupting RAS-effector interactions in a GTP-dependent manner, thereby inhibiting RAS activation, including KRAS, HRAS, and NRAS, regardless of mutational status.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutation-specific KRAS inhibitors are used, then inhibition of specific KRAS mutants is achieved, but patients develop resistance and secondary mutations in other RAS isoforms
Solution Approach 1:
The compound tegaserod is designed to inhibit multiple RAS isoforms (KRAS, HRAS, NRAS) simultaneously rather than targeting a single mutant variant. This multi-functional approach prevents resistance development by blocking alternative RAS pathways that would otherwise compensate for inhibition of a specific mutant form.
Solution Approach 2:
Tegaserod acts as an intermediary compound that disrupts the interaction between RAS proteins and their effectors at the plasma membrane. By targeting the RAS-effector interface rather than the RAS mutant structure directly, it prevents resistance mutations from altering the binding interface.
2Reliability
If RAS inhibitors are used to treat RAS-related disorders, then RAS oncogene activation is inhibited, but toxicity and limited specificity remain challenges
Solution Approach 1:
The compound tegaserod exhibits selective inhibition of RAS oncogene activation at specific concentrations while sparing normal cellular functions. The local quality principle is applied by optimizing the compound's affinity and selectivity for pathological RAS states versus physiological conditions, thereby achieving therapeutic efficacy with minimized toxicity.
3Ease of operation
If standard therapies are used for RAS-related disorders, then treatment is provided, but resistance to treatment develops
Solution Approach 1:
Tegaserod, originally developed for gastrointestinal disorders, is repurposed to treat RAS-related cancers and inflammatory conditions. This repurposing converts a existing safe compound into a new therapeutic application, leveraging its established safety profile while addressing resistance issues through its unique mechanism of action on RAS effectors.
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).