Inhibition of ABC‐Transporters by in silico Identified Small Molecules

Multidrug resistance (MDR) is a complex phenotype characterized by simultaneous resistance to structurally and functionally dissimilar drugs. MDR is frequently associated with overexpression of transmembrane efflux proteins belonging to the ATP‐binding cassette (ABC) transporter superfamily including P‐glycoprotein (P‐gp), multidrug resistance associated protein (MRP1), and breast cancer resistance protein (BCRP). Normally expressed at tissue barriers, these proteins protect vulnerable cells from xenobiotic attack by pumping a wide range of toxins out of the cell. Unfortunately, this broad substrate range, characteristic of these transporters, poses a major obstacle to the successful chemotherapeutic treatment of cancers since the majority of clinically relevant chemotherapeutic drugs can be effluxed by P‐gp, MRP1, and BCRP. Treatment and prevention of MDR have been studied extensively for decades, and yet, there are still no effective FDA‐approved therapies available. Using targeted molecular dynamics and massively parallel drug docking studies, we have screened millions of drug‐like molecules and identified hundreds of compounds that are predicted to inhibit P‐gp by specifically interacting with its ATP binding domain. We have previously shown that of four of these in silico identified compounds inhibited P‐gp catalyzed ATP hydrolysis (Brewer, F. K., Follit, C. A., Vogel, P. D., & Wise, J. G. (2014) Molecular Pharmacology, 86(6), 716–726). When tested in cell culture, three of these compounds restored chemotherapeutic sensitivity in a multidrug resistant human cancer cell line which overexpresses P‐gp (Follit CA, Brewer FK, Wise JG, Vogel PV (2015) Pharmacology Research & Perspectives 3(5): e00170). In this study, we expand our cell culture screening to evaluate 46 potential inhibitors identified by our in silico screening methods and report that over 30% of these compounds restored chemosensitivity to MDR human cancer cell lines. The best of these compounds will be further investigated to determine toxicity and specificity. With future chemical optimization, we are working towards developing powerful co‐therapeutics to treat and prevent MDR in human cancers. Support or Funding Information This work is supported by NIH NIGMS [Grants R15‐GM094771‐01A1 and R15‐GM094771‐02] to PDV and JGW, SMU University Research Council, SMU Engaged Learning program, the SMU Center for Drug Discovery, Design and Delivery, the Communities Foundation of Texas, and a private gift from Ms. Suzann Ruff of Dallas, Texas.