Flavonoid Monomers as Potent, Nontoxic, and Selective Modulators of the Breast Cancer Resistance Protein (ABCG2)

Iris L.K. Wong, Xuezhen Zhu, Kin Fai Chan, Zhen Liu, Chin Fung Chan, Tsun Sing Chow, Tsz Cheung Chong, Man Chun Law, Jiahua Cui, Larry M.C. Chow, Tak Hang Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review


We synthesize various substituted triazole-containing flavonoids and identify potent, nontoxic, and highly selective BCRP inhibitors. Ac18Az8, Ac32Az19, and Ac36Az9 possess m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone moiety and substituted triazole at C-4′ of the B-ring. They show low toxicity (IC50 toward L929 > 100 μM), potent BCRP-inhibitory activity (EC50 = 1-15 nM), and high BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 67-714). They inhibit the efflux activity of BCRP, elevate the intracellular drug accumulation, and restore the drug sensitivity of BCRP-overexpressing cells. Like Ko143, Ac32Az19 remarkably exhibits a 100% 5D3 shift, indicating that it can bind and cause a conformational change of BCRP. Moreover, it significantly reduces the abundance of functional BCRP dimers/oligomers by half to retain more mitoxantrone in the BCRP-overexpressing cell line and that may account for its inhibitory activity. They are promising candidates to be developed into combination therapy to overcome MDR cancers with BCRP overexpression.

Original languageEnglish
Pages (from-to)14311-14331
Number of pages21
JournalJournal of Medicinal Chemistry
Issue number19
Publication statusPublished - 14 Oct 2021

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this