Abstract
Chronic myeloid leukemia treatment faces the challenge of resistance to BCR-ABL1 tyrosine kinase inhibitors. To address this, we rationally designed six new imatinib-derived compounds 2(a-f) by replacing the quinoline moiety with a [1,2,4]triazolo[1,5-a]pyrimidine scaffold via classical bioisosterism. The compounds were efficiently synthesized and characterized. Biological evaluation revealed that compound 2a exhibited cytotoxic activity in BCR-ABL1-positive K562 cells (47% viability inhibition at 10 µM, IC(50) = 9.7 µM). However, enzymatic assays demonstrated that 2a does not directly inhibit the wild-type ABL1 kinase, unlike IMT. This finding, coupled with its cytotoxicity in nontumorigenic WSS-1 cells, indicates an alternative, off-target mechanism. A clear structure-activity relationship identified the detrimental effect of a -CF(3) substitution. Overall, this work applies bioisosteric replacement to generate a new chemotype and uncovers a mechanistically divergent lead. The distinct, ABL1-independent mechanism of compound 2a establishes a solid foundation for future optimization and highlights its potential as a starting point for developing novel antimyeloproliferative agents with a different therapeutic profile.