Diaryl Macrocyclic Kinase Inhibitors Overcoming Drug Resistance
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Solution Overview
Problem
Current treatments for cancers driven by TRK fusion proteins, ALK, and ROS1 kinase are limited by drug resistance, with existing inhibitors failing to effectively overcome bypass activation and epithelial mesenchymal transition, leading to reduced long-term efficacy.
Innovation Solution
Development of a diaryl macrocyclic compound with specific structural features that inhibit tyrosine kinases, including TRKA, TRKB, TRKC, ALK, ROS1, and other kinases, capable of overcoming drug resistance and penetrating the blood-brain barrier, formulated into a pharmaceutical composition for oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing TRK, ALK, and ROS1 kinase inhibitors are used for cancer treatment, then initial therapeutic effect is achieved, but drug resistance develops leading to reduced long-term efficacy
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of kinase inhibitors to create new compounds with altered binding properties. The diaryl macrocyclic compound structure (Formula 1) represents a significant structural parameter change from existing inhibitors, enabling the compound to maintain efficacy against resistant mutations while preserving target binding affinity.
Solution Approach 2:
The invention achieves universality by designing a multi-functional inhibitor that can simultaneously target multiple kinase family members (TRKA, TRKB, TRKC, ALK, ROS1, and other kinases). This multi-target capability allows the single compound to address multiple resistance mechanisms and maintain broad therapeutic effectiveness against diverse cancer types and resistance profiles.
2Adaptability or versatility
If current ALK inhibitors are administered to overcome drug resistance, then some resistance mechanisms are addressed, but bypass activation and epithelial mesenchymal transition remain unovercome
Solution Approach 1:
The diaryl macrocyclic compound achieves universality by simultaneously inhibiting multiple kinase targets involved in different resistance mechanisms. The compound can inhibit both the primary target kinases and alternative pathways, including those involved in bypass activation and epithelial-mesenchymal transition, providing comprehensive coverage against diverse resistance mechanisms through a single multi-functional agent.
Solution Approach 2:
The invention applies dynamics by creating a flexible molecular structure that can adapt to different binding configurations. The macrocyclic framework with variable substituents (R1-R6, L1-L2, X, Z, n parameters) allows the compound to dynamically adjust its conformation and binding mode to effectively inhibit diverse kinase targets and resistance pathways.
3Reliability
If new-generation TRK inhibitors are developed to overcome NTRK mutations, then resistance to mutated targets is reduced, but the complexity of addressing multiple resistance mutations increases
Solution Approach 1:
The patent resolves the complexity issue by creating a universal inhibitor that addresses multiple NTRK mutations simultaneously. Rather than developing separate inhibitors for each mutation, the diaryl macrocyclic compound structure is designed to maintain binding affinity across various NTRK1, NTRK2, and NTRK3 mutations, simplifying the therapeutic approach while maintaining high reliability against mutated targets.
4Productivity
If Crizotinib is used for ROS1-positive NSCLC, then initial treatment response is achieved, but acquired drug resistance emerges at specific mutation sites
Solution Approach 1:
The invention applies parameter changes by fundamentally altering the chemical structure from Crizotinib to a diaryl macrocyclic framework. This structural parameter change enables the new compound to maintain productive inhibition of wild-type ROS1 while simultaneously addressing resistance mutations at sites such as ROS1 G2032 and ROS1 L2026M, thereby sustaining treatment efficacy where Crizotinib fails.
Data Source
AI summary
The present invention provides a compound as represented by formula (1) or a pharmaceutically acceptable salt, a solvate, an active metabolite, a polymorph, an isotope label, an isomer or a prodrug thereof. The present invention also provides a pharmaceutical composition containing the same and the use of the compound and the pharmaceutical composition in preparation of drugs for treating tyrosine kinase-mediated diseases. The compound and the pharmaceutical composition comprising same provided by the present disclosure have significant tyrosine kinase inhibitory activity, can overcome tumor drug resistance, and break through blood-brain barrier, also have excellent pharmacokinetic properties and excellent oral bioavailability, and can be administered in a small dosage, thereby reducing treatment costs and possible side effects to a patient. Thus, the application potential is very great.