Chiral Diaryl Macrocycle Kinase Inhibitor for ALK Resistance
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Solution Overview
Problem
Current ALK inhibitors face challenges with drug resistance due to secondary mutations and bypass signaling pathways, necessitating the development of polypharmacological agents that can target multiple kinases, including ALK, ROS1, TRK, JAK2, and SRC, to effectively treat cancers with genetic alterations.
Innovation Solution
The compound (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one is developed as a potent small-molecule multi-target kinase inhibitor, demonstrating activity against wild-type and mutant ALK, ROS1, TRK, JAK2, and SRC kinases, offering a pharmacological approach to inhibit these kinases and overcome resistance mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If single-target ALK inhibitors are used, then initial therapeutic effect is achieved, but drug resistance develops due to secondary mutations and bypass signaling
Solution Approach 1:
The patent applies polypharmacology by designing a single small molecule that can simultaneously inhibit multiple kinases including ALK, ROS1, TRK, JAK2, and SRC. This multi-functional approach allows the compound to target primary oncogene drivers while also blocking bypass signaling pathways and mutant forms, thereby maintaining therapeutic efficacy and preventing drug resistance mechanisms that would otherwise limit response duration
2Reliability
If polypharmacological agents targeting multiple kinases are developed, then resistance mechanisms are overcome, but compound complexity increases
Solution Approach 1:
The patent merges multiple kinase inhibition activities into a single small molecule compound. By combining pharmacophore elements that confer activity against ALK, ROS1, TRK, JAK2, and SRC into one integrated molecular structure, the invention achieves polypharmacological effects without requiring combination therapy of multiple separate agents, thus managing complexity while maintaining multi-target capability
Data Source
AI summary
This disclosure relates to the use of certain diaryl macrocycle compounds, specifically (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one in the treatment of disease in mammals. This disclosure also relates to compositions including such compounds, and to methods of using such compositions in the treatment of diseases in mammals, especially in humans.