New inhibitors of ABCG2 identified by high-throughput screening

作者：Curtis J. Henrich, Robert W. Robey, Heidi Rose Bokesch, Susan E. Bates, Suneet Shukla, Suresh V. Ambudkar, Michael C. Dean, James Brislin McMahon · 发表于：Molecular Cancer Therapeutics · 年份：2007 · DOI：10.1158/1535-7163.mct-07-0352 · 被引用次数：66 · 研究领域：Drug Transport and Resistance Mechanisms、Cancer therapeutics and mechanisms、Pharmacogenetics and Drug Metabolism

In order to identify novel inhibitors of the ATP-binding cassette transporter, ABCG2, a high-throughput assay measuring the accumulation of the ABCG2 substrate pheophorbide a in ABCG2-overexpressing NCI-H460 MX20 cells was used to screen libraries of compounds. Out of a library of 7,325 natural products and synthetic compounds from the National Cancer Institute/Developmental Therapeutics Program collection, 18 were found to inhibit ABCG2 at 10 micromol/L. After eliminating flavonoids and compounds of limited availability from the 18 original compounds, 10 of the 11 remaining compounds reversed mitoxantrone resistance in NCI-H460/MX20 cells and prevented ABCG2-mediated BODIPY-prazosin transport in ABCG2-transfected HEK293 cells, confirming an interaction with ABCG2. Based on the activity profiles and the availability of materials, five inhibitors were examined for their ability to compete with [(125)I]iodoarylazidoprazosin labeling of ABCG2, increase binding of the anti-ABCG2 antibody 5D3, and prevent P-glycoprotein or multidrug resistance protein 1-mediated transport. At a concentration of 20 micromol/L, all of the compounds reduced iodoarylazidoprazosin labeling by 50% to 80% compared with controls. All five compounds also increased 5D3 labeling of ABCG2, indicating that these compounds are inhibitors but not substrates of ABCG2. None of the compounds affected P-glycoprotein-mediated rhodamine 123 transport, whereas three affected multidrug resistance protein-1-mediated calc...