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 1,2,4triazolo1,5‐ 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.
Moura et al. (2026) studied this question.