Macrocyclic RAS Inhibitors for KRAS G12D and G12V Mutations
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Solution Overview
Problem
Current treatments for KRAS G12D and G12V mutations in pancreatic cancer, colorectal cancer, NRAS mutations in melanoma, and HRAS mutations in head and neck cancer lack effective targeted drugs, necessitating the development of highly active and low-toxicity inhibitors for RAS proteins.
Innovation Solution
Development of macrocyclic compounds represented by formula (18) or their derivatives, stereoisomers, pharmaceutically acceptable salts, solvates, or prodrugs, which exhibit high activity and low toxicity, with specific substitutions and functional groups that inhibit RAS proteins, including KRAS G12D and G12V mutations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If targeted drugs are developed for KRAS G12C mutation, then treatment effectiveness is improved, but no effective drugs exist for other RAS mutations (KRAS G12D, G12V, NRAS, HRAS)
Solution Approach 1:
The patent designs macrocyclic compounds with a universal binding mechanism that can inhibit multiple RAS protein variants (KRAS G12D, G12V, NRAS, HRAS) through a single class of inhibitors, eliminating the need for separate targeted drugs for each mutation type and achieving broad-spectrum RAS inhibition
2Reliability
If conventional RAS inhibitors are used, then RAS protein inhibition is achieved, but toxicity and side effects increase
Solution Approach 1:
The patent optimizes the macrocyclic compound structure by changing key parameters including introducing specific functional groups (carboxylic acid, hydroxyl, amino), adjusting molecular weight to 200-500 Da, controlling logP value between -1 and 3, and optimizing hydrogen bonding capabilities to achieve high RAS inhibition activity with reduced toxicity and side effects
Data Source
Figure 1~2
AI summary
Compounds represented by formula (I) or stereoisomers thereof, or pharmaceutically acceptable salts, solvates or prodrugs thereof, each group in the formula being defined in the description, a pharmaceutical composition comprising the compounds and the use thereof in the preparation of drugs used for preventing and/or treating diseases or disorders (such as cancer) related to RAS protein activity.