Advances in Targeting BCR-ABLT315I Mutation with Imatinib Derivatives and Hybrid Anti-Leukemic Molecules

Resistance to imatinib remains a therapeutic challenge, largely driven by point mutations within the kinase domain of the <i>BCR-ABL</i>, among which the <i>T315I</i> 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 <i>BCR-ABL^T315I</i>. 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 <i>p38</i> kinase modulators, demonstrates additional opportunities for overcoming resistance. Combination strategies, such as vorinostat with ponatinib, provide complementary therapeutic avenues. Natural-product-inspired approaches utilizing fungal metabolites provided structurally diverse scaffolds that could engage sterically constrained mutant kinases. Hybrid molecules derived from approved <i>TKIs</i>, including GNF-7, olverembatinib, and HG-7-85-01, exemplify rational design trends that balance efficacy with improved safety. Molecular modeling continues to deepen understanding of ligand engagement within the <i>T315I</i>-mutated active site, supporting the development of next-generation inhibitors. In this review, we summarized recent progress in the design, optimization, and biological evaluation of small molecules targeting the <i>BCR-ABL^T315I</i> mutation.