Abstract
Based on literature reports of the last two decades, a computer-aided pattern analysis (C@PA) was implemented for the discovery of novel multitarget ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) inhibitors. C@PA included basic scaffold identification, substructure search and statistical distribution, as well as novel scaffold extraction to screen a large virtual compound library. Over 45,000 putative and novel broad-spectrum ABC transporter inhibitors were identified, from which 23 were purchased for biological evaluation. Our investigations revealed five novel lead molecules as triple ABCB1, ABCC1, and ABCG2 inhibitors. C@PA is the very first successful computational approach for the discovery of promiscuous ABC transporter inhibitors.
Highlights
Expression of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters in multidrug-resistant cancer remains a huge obstacle in cancer chemotherapy
While 1,2,5-oxadiazoles59−62 have frequently been reported as ABCB159,60,62 and ABCC1 inhibitors,61,62 1,2,4-oxadiazoles63−65 have only once been reported as selective ABCG2 inhibitors65 or reversers of ABCB1, ABCC1, or ABCG2-mediated multidrug resistance (MDR).63,64 1,3,4
Thiadiazoles have only once been reported in association with selective, dual, or triple ABCB1, ABCC1, and ABCG2 inhibition
Summary
Expression of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters in multidrug-resistant cancer remains a huge obstacle in cancer chemotherapy. Amongst these are the three well-studied transporters ABCB1 (P-glycoprotein, P-gp), ABCC1 (multidrug resistance-associated protein 1, MRP1), and ABCG2 (breast cancer resistance protein, BCRP), for which a bunch of potent (and mostly specific) small-molecule inhibitors has been generated over the last four decades.− clinical studies approaching one single transporter with selective and highly potent agents have mostly failed.− Two concluding postulations emerged very recently: (i) ABC transporters have a differing (individual) substrate range, which increases cross-resistance in case of their coexpression.6,8 These individual substrate ranges combined cover almost the whole range of today’s applied antineoplastic agents;− (ii) ABC transporters have an overlapping (collective) substrate range, enabling them to compensate for the selective inhibition and/or downregulation of their functional counterpart(s).
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