Department of Integrative Structural and Computational Biology , The Scripps Research Institute , La Jolla , California 92037 , United States.
J Med Chem. 2018 Jun 28;61(12):5108-5121. doi: 10.1021/acs.jmedchem.7b01457. Epub 2017 Dec 28.
Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope of circumventing MDR, with only limited success. Alternative strategies are actively pursued, such as the modification of existing drugs, development of new drugs, or combination of novel drug delivery agents to evade P-gp-dependent efflux. Despite the importance and numerous studies, these efforts have mostly been undertaken without a priori knowledge of how drugs interact with P-gp at the molecular level. This review highlights and discusses progress toward and challenges impeding drug development for inhibiting or evading P-gp in the context of our improved understanding of the structural basis and mechanism of P-gp-mediated MDR.
多药耐药性（MDR）是癌症化疗失败的主要原因。由于在癌细胞中过表达，多药耐药相关蛋白（P-gp）是一种混杂的药物外排泵，已被广泛研究与 MDR 的关系。已经在临床试验中研究了几种 P-gp 抑制剂或调节剂，希望能够克服 MDR，但只有有限的成功。目前正在积极探索替代策略，例如修改现有药物、开发新药或结合新型药物输送剂来逃避 P-gp 依赖性外排。尽管这些努力非常重要，并且已经进行了大量研究，但这些努力大多是在没有事先了解药物在分子水平上与 P-gp 相互作用的情况下进行的。这篇综述强调并讨论了在我们对 P-gp 介导的 MDR 的结构基础和机制有了更好的理解的情况下，在抑制或逃避 P-gp 方面药物开发的进展和阻碍因素。
