Macrocyclic RAS Inhibitors for Broad Mutant Coverage

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Solution Overview

Problem

Existing treatments for RAS mutations beyond KRASG12C are limited, and there is a need for therapies that can effectively inhibit multiple RAS mutants due to the high affinity of RAS for GTP and lack of accessible binding pockets, leading to drug resistance and therapeutic challenges.

Innovation Solution

Development of novel macrocyclic compounds that inhibit multiple RAS mutants by targeting various RAS isozymes, including KRAS, NRAS, and HRAS, designed to overcome drug resistance and provide a single agent for concurrent inhibition.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If allele-selective inhibitors are used to treat KRASG12C mutations, then therapeutic efficacy is improved for specific mutants, but drug resistance emerges and therapeutic utility is curtailed

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtherapeutic utility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops macrocyclic compounds that function as universal inhibitors across multiple RAS mutant types (KRASG12C, KRASG12D, KRASG12V, NRASQ61K, NRASG12C, HRASG12V), transforming a single-agent therapy from mutant-specific to broadly applicable, thereby resolving the contradiction between efficacy for specific mutants and overall therapeutic utility

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

Instead of designing separate inhibitors for each RAS mutant (specific approach), the patent inverts the strategy by creating a single macrocyclic compound that binds to multiple RAS mutants simultaneously (broad approach), achieving versatility without sacrificing efficacy

Inventive Principle:

Principle #13The other way round (Inversion)

2Adaptability or versatility

If multiple separate inhibitors are developed for different RAS mutants, then coverage of various mutants is improved, but device complexity and treatment regimen complexity increase

Engineering Contradiction:

Improvecoverage of RAS mutantsVSAvoidtreatment regimen complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent merges the functions of multiple mutant-specific inhibitors into a single macrocyclic compound that concurrently targets multiple RAS mutants, simplifying the treatment regimen from multiple drugs to one agent while maintaining comprehensive mutant coverage

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The macrocyclic compound serves multiple therapeutic functions simultaneously by inhibiting various RAS mutants through a single molecular entity, eliminating the need for complex combination therapies

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20260078134A1Macrocyclic Compounds as RAS Inhibitors

Publication Date: 2026.03.19 BEONE MEDICINES I GMBH

AI summary

Provided herein are compounds having the following structure:or pharmaceutically acceptable salts, hydrates, or solvates thereof, wherein the substituents are as defined herein, their pharmaceutical compositions and uses for modulating the activity of multiple RAS mutants.