Design, Synthesis, and Biological Evaluation of Efflux-Resistant Imatinib Derivatives

Resistance to imatinib, a first-line BCR-ABL1 tyrosine
kinase inhibitor
for chronic myeloid leukemia, is frequently mediated by drug efflux
through P-glycoprotein (P-gp) overexpression. We report the design,
synthesis, and evaluation of eight novel imatinib derivatives modified
at the piperazine terminus with efflux resistance breaker (ERB) fragments
to reduce P-gp-mediated efflux. In silico docking
against cryo-EM P-gp structures predicted increased hydrophobic interactions
and enhanced occupancy at the access tunnel, indicative of efflux
inhibition. Compound 8 showed potency comparable to imatinib
in BCR-ABL1+ K562 cells and a lower LC50 fold
change in resistant K562/DOX cells, suggesting reduced efflux susceptibility.
Accumulation assays confirmed the improved intracellular retention
of compound 8. Compound 9 displayed increased
potency in resistant cells, correlating with higher intracellular
levels despite modest kinase inhibition. Verapamil assays confirmed
reduced efflux liability for compounds 8 and 13. Compound 8 also showed a positive therapeutic index.
These findings support rational design to mitigate efflux-mediated
resistance.