BMS-599626, a highly selective pan-her kinase inhibitor, antagonizes ABCG2-mediated drug resistance

Yunali V. Ashar, Jingchun Zhou, Pranav Gupta, Qiu Xu Teng, Zi Ning Lei, Sandra E. Reznik, Sabrina Lusvarghi, John Wurpel, Suresh V. Ambudkar, Zhe Sheng Chen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Multidrug resistance (MDR) associated with the overexpression of ABC transporters is one of the key causes of chemotherapy failure. Various compounds blocking the function and/or downregulating the expression of these transporters have been developed over the last few decades. However, their potency and toxicity have always been a concern. In this report, we found that BMS-599626 is a highly potent inhibitor of the ABCG2 transporter, inhibiting its efflux function at 300 nM. Our study repositioned BMS-599626, a highly selective pan-HER kinase inhibitor, as a chemosensitizer in ABCG2-overexpressing cell lines. As shown by the cytotoxicity assay results, BMS-599626, at noncytotoxic concentrations, sensitizes ABCG2-overexpressing cells to topotecan and mitoxantrone, two well-known substrates of ABCG2. The results of our radioactive drug accumulation experiment show that the ABCG2-overexpressing cells, treated with BMS-599626, had an increase in the accumulation of substrate chemotherapeutic drugs, as compared to their parental subline cells. Moreover, BMS-599626 did not change the protein expression or cell surface localization of ABCG2 and inhibited its ATPase activity. Our in-silico docking study also supports the interaction of BMS-599626 with the substrate-binding site of ABCG2. Taken together, these results suggest that administration of chemotherapeutic drugs, along with nanomolar concentrations (300 nM) of BMS-599626, may be effective against ABCG2-mediated MDR in clinical settings.

Original languageEnglish (US)
Article number2502
Pages (from-to)1-15
Number of pages15
Issue number9
StatePublished - Sep 2020


  • ABC transporters
  • ABCG2
  • BMS-599626
  • Chemotherapy
  • HER kinase inhibitor
  • Multidrug resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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