Research Group of Drug Development, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
Department of Clinical Pharmacy, Institute of Pharmacy, Ernst Moritz Arndt University Greifswald, 17489 Greifswald, Germany.
Molecules. 2020 Dec 22;26(1):18. doi: 10.3390/molecules26010018.
Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept.
尽管癌症的靶向治疗已经取得了进展，但多药耐药（MDR）问题仍然没有得到解决。大多数转移性癌症患者都死于 MDR。已经开发出的抑制剂针对跨膜外排泵作为 MDR 的主要原因，但最早开发的最突出和最长已知的外排泵 P-糖蛋白（P-gp）的抑制剂令人失望。这些抑制剂在不知道治疗肿瘤中 P-gp 表达的情况下被使用。因此，在相应外排泵表达的情况下，重新考虑将跨膜外排泵抑制剂用于临床环境是一种有前途的策略。我们发现了由 ABCC4 基因编码的对称外排泵 MRP4 的新型对称抑制剂。MRP4 参与了许多对抗癌药物有耐药性的癌症。在 MRP4 过表达细胞系测定中，所有化合物的活性均优于最著名的 MRP4 抑制剂 MK571，并且活性可能与对称分子结构内芳香残基的各种取代模式有关。已经证明最好的化合物之一能够克服 MRP4 介导的耐药性，在细胞系模型中恢复抗癌药物敏感性，以此作为概念验证。
