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

  • J Med Chem. 2021 Oct 14;64(19):14311-14331. doi: 10.1021/acs.jmedchem.1c00779.
Iris L K Wong  1 ,  Xuezhen Zhu  1 ,  Kin-Fai Chan  1 ,  Zhen Liu  1 ,  Chin-Fung Chan  1 ,  Tsun Sing Chow  1 ,  Tsz Cheung Chong  1 ,  Man Chun Law  1 ,  Jiahua Cui  2 ,  Larry M C Chow  1 ,  Tak Hang Chan  1  3
Affiliations
  • 1. Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery, Hong Kong Polytechnic University, Hong Kong SAR 999077, China.
  • 2. School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3. Department of Chemistry, McGill University, Montreal, Quebec H3A 2K6, Canada.
PMID: 34606270 DOI: 10.1021/acs.jmedchem.1c00779
Abstract

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.

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