Advances in Targeting BCR-ABLT315I Mutation with Imatinib Derivatives and Hybrid Anti-Leukemic Molecules
Aleksandra Tuzikiewicz, Wiktoria Wawrzyniak, Andrzej Kutner, Teresa Żołek
TL;DR
This review discusses recent advancements in developing safer and more effective drugs to target the BCR-ABLT315I mutation, a major cause of resistance in leukemia treatment.
Contribution
The paper provides a comprehensive overview of novel molecular designs and strategies for overcoming BCR-ABLT315I resistance in leukemia.
Findings
Aminopyrimidine-derived scaffolds and their derivatives show improved activity against BCR-ABLT315I.
Benzothiazole–picolinamide hybrids with urea-based pharmacophores enhance potency against the T315I mutation.
Natural-product-inspired fungal metabolites offer structurally diverse options for targeting mutant kinases.
Abstract
Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the BCR-ABL, among which the T315I substitution constitutes the most clinically significant barrier. Ponatinib effectively inhibits this mutant form but is limited by dose-dependent cardiovascular toxicity, prompting efforts to develop safer and more selective agents. Recent advances highlight aminopyrimidine-derived scaffolds and their evolution into thienopyrimidines, oxadiazoles, and pyrazines with improved activity against BCR-ABLT315I. Further progress has been achieved with benzothiazole–picolinamide hybrids incorporating a urea-based pharmacophore, which benefit from strategic hinge-region substitutions and phenyl linkers that enhance potency. Parallel research into dual-mechanism inhibitors, including Aurora and p38 kinase modulators, demonstrates additional…
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Taxonomy
TopicsChronic Myeloid Leukemia Treatments · Protein Degradation and Inhibitors · Click Chemistry and Applications