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

  • J Med Chem. 2025 Nov 13;68(21):22619-22632. doi: 10.1021/acs.jmedchem.5c01596.
Madiha M Chowdhury  1 ,  Priantha Pretheshan  1 ,  Nasima S Chowdhury  1 ,  Paolo Andriollo  1 ,  Ajit J Shah  2 ,  Ben Forbes  1 ,  Chris Pepper  3 ,  Khondaker Miraz Rahman  1
Affiliations
  • 1. Institute of Pharmaceutical Science, King's College London, London SE1 9NH, U.K.
  • 2. Department of Natural Sciences, University of Middlesex, The Burroughs, Hendon, London NW4 4BT, U.K.
  • 3. Brighton and Sussex Medical School, University of Brighton and University of Sussex, Brighton BN1 9PX, U.K.
PMID: 41137772 DOI: 10.1021/acs.jmedchem.5c01596
Abstract

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.

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