Macrocyclic RAS Inhibitors for Broad-Spectrum Mutation Coverage
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Solution Overview
Problem
Current targeted therapeutic drugs are ineffective for cancer types with KRAS mutations other than KRASG12C, such as G12D and G12V, and there is a need for broad-spectrum RAS inhibitors that can target various RAS mutations, including NRAS, to address the high prevalence of RAS-mutant cancers.
Innovation Solution
Development of macrocyclic compounds that form ternary complexes with chaperones CypA and RAS(ON), inhibiting the RAS-RAF-MEK-ERK signaling pathway by blocking RAF binding, thereby providing broad-spectrum inhibition of RAS-mutant tumors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If targeted covalent inhibitors are developed for specific KRAS mutations (e.g., KRASG12C), then high efficacy is achieved for that specific mutation, but the drug becomes ineffective for other RAS mutation types
Solution Approach 1:
The macrocyclic compound is designed to form ternary complexes with CypA and multiple RAS mutation types simultaneously, enabling a single drug to target various RAS mutants (KRASG12C, KRASG12D, KRASG12V, KRASG13C, NRAS, etc.) through a universal mechanism of blocking RAF binding to RAS(ON), thus achieving broad-spectrum coverage while maintaining efficacy
Solution Approach 2:
The macrocyclic compound acts as an intermediary that facilitates the formation of ternary complexes between CypA chaperone and RAS(ON) proteins. This intermediary mechanism allows the drug to indirectly inhibit multiple RAS mutation types by disrupting the RAF-RAS interaction rather than directly binding to specific mutation sites, thereby achieving both efficacy and broad-spectrum coverage
2Adaptability or versatility
If macrocyclic compounds forming ternary complexes with CypA and RAS(ON) are developed, then broad-spectrum inhibition of RAS-mutant tumors is achieved, but the mechanism complexity increases
Solution Approach 1:
The macrocyclic compound serves as a mediator that simplifies the complex ternary complex formation process by providing a pre-organized structure that naturally facilitates simultaneous binding to CypA and RAS(ON). The macrocyclic framework contains key functional groups (hydrogen bond donors/acceptors, hydrophobic regions, cationic residues) positioned to interact with both proteins, reducing the entropic penalty and kinetic barriers of ternary complex formation while achieving broad-spectrum inhibition
Data Source
AI summary
The present disclosure discloses a class of macrocyclic derivatives, and specifically discloses a compound shown in formula (VI), a stereoisomer thereof, and a pharmaceutically acceptable salt thereof.