Discovery of Novel Flavonoid Dimers to Reverse Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediated Drug Resistance in Cancers Using a High Throughput Platform with "click Chemistry"

Iris L.K. Wong, Xuezhen Zhu, Kin Fai Chan, Man Chun Law, Aya M.Y. Lo, Xuesen Hu, Larry M.C. Chow, Tak Hang Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

12 Citations (Scopus)


A 300-member flavonoid dimer library of multidrug resistance-associated protein 1 (MRP1, ABCC1) modulators was rapidly assembled using "click chemistry". Subsequent high-throughput screening has led to the discovery of highly potent (EC50 ranging from 53 to 298 nM) and safe (selective indexes ranging from >190 to >1887) MRP1 modulators. Some dimers have potency about 6.5- to 36-fold and 64- to 358-fold higher than the well-known MRP1 inhibitors, verapamil, and MK571, respectively. They inhibited DOX efflux and restored intracellular DOX concentration. The most potent modulator, Ac3Az11, was predicted to bind to the bipartite substrate-binding site of MRP1 in a competitive manner. Moreover, it provided sufficient concentration to maintain its plasma level above its in vitro EC50 (53 nM for DOX) for about 90 min. Overall, we demonstrate that "click chemistry" coupled with high throughput screening is a rapid, reliable, and efficient tool in the discovery of compounds having potent MRP1-modualting activity.

Original languageEnglish
Pages (from-to)9931-9951
Number of pages21
JournalJournal of Medicinal Chemistry
Issue number22
Publication statusPublished - 21 Nov 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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