Targeted Inhibitors of P‐glycoprotein Overcome Multidrug Resistance in Human Cancer Cell Lines

Abstract

Multidrug resistance (MDR), the intrinsic or acquired simultaneous resistance to structurally and chemically unrelated drugs, is arguably the largest barrier to the successful chemotherapeutic treatment of cancer. The best studied mechanism of MDR is due to the overexpression of ABC‐transporter member P‐glycoprotein (P‐gp). All ABC‐transporters utilize ATP hydrolysis to actively export substrates out of the cell, but P‐gp is exceptional in that its substrates are diverse enough to include the majority of clinically relevant chemotherapeutics. Researchers have searched for drugs to inhibit P‐gp for decades and largely failed because the majority interacted with the drug‐binding domain of P‐gp and were themselves transported. Using targeted molecular dynamic simulations and massively parallel drug docking studies, we identified novel compounds that inhibit P‐gp by specifically targeting the ATP binding domain of P‐gp. Biochemical and biophysical studies have confirmed ATP hydrolysis is inhibited by these novel compounds. In the studies reported here, we have evaluated these compounds for their ability to restore drug sensitivity to MDR human cancer cell lines that overexpress P‐gp. Effects on other ABC‐transporters capable of conferring the MDR phenotype are being evaluated and lead compounds are undergoing chemical optimization to develop co‐therapeutics capable of reversing MDR in human cancers.This work is supported by NIH NIGMS [Grant 1R15‐GM094771‐01A1] to PDV and JGW, SMU Research Council, SMU Dean's Research Council, the SMU Center for Drug Discovery, Design and Delivery, and the Communities Foundation of Texas, Dallas.