Diarylacetylene Hydrazides Inhibiting T315I Mutant Kinase
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Solution Overview
Problem
Current tyrosine kinase inhibitors, such as imatinib and its second-generation derivatives, face challenges in effectively targeting the T315I mutation, leading to drug resistance in cancer treatment, particularly in chronic myelogenous leukemia, and are associated with side effects like cardiac toxicity and off-target toxicities.
Innovation Solution
Development of novel diarylacetylene hydrazides that act as potent inhibitors of Abl tyrosine kinase, including its mutated forms, including the T315I mutant, offering a safer and more effective alternative with reduced cardiac toxicity and broader kinase inhibition specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current tyrosine kinase inhibitors (imatinib and second-generation derivatives) are used to target Abl kinase, then tyrosine kinase activity is inhibited, but they fail to effectively target the T315I mutation leading to drug resistance
Solution Approach 1:
The patent modifies the chemical structure of tyrosine kinase inhibitors by introducing a diarylacetylene hydrazide core with specific substituents (aromatic rings, heterocyclic groups, and varying functional groups at R1-R6 positions). These structural parameter changes enable the compound to effectively bind to and inhibit the T315I mutant Abl kinase, overcoming the drug resistance that plagues previous generations of inhibitors.
2Reliability
If current tyrosine kinase inhibitors are used at higher doses to overcome resistance, then inhibition efficacy may improve, but cardiac toxicity and off-target toxicities increase
Solution Approach 1:
The patent employs selective inhibition by designing compounds with specific molecular characteristics that target Abl kinase and its T315I mutant with high affinity while sparing other kinases. The diarylacetylene hydrazide structure with particular substituent patterns (such as quinolinyl, pyridinyl, or benzothiazolyl groups) provides local specificity that achieves potent inhibition efficacy without the broad off-target effects that cause cardiac toxicity at higher doses.
Data Source
AI summary
The present invention relates to novel diarylacetylene hydrazide compounds of formula (I) or pharmaceutically acceptable salt thereof, as tyrosine kinase inhibitors, the process for their preparation, and to the use of the compounds of formula (I) in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders related to tyrosine kinases, in warm-blooded animals