Cancer Centre, Faculty of Health Sciences, University of Macau, Macau.
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing 401331, PR China.
Drug Discov Today. 2021 Mar;26(3):836-844. doi: 10.1016/j.drudis.2021.01.003. Epub 2021 Jan 12.
Cancer cells metabolize glucose via anaerobic glycolysis, with lactate formed in the cytosol as the end-product. To avoid intercellular acidification, excessive lactate and proton are excreted by monocarboxylate transporters (MCTs), which are often overexpressed in different malignant cancers. Targeting the MCT-mediated lactate/proton efflux makes MCTs a potentially interesting anticancer target. Although X-ray co-crystal structures of human MCTs with inhibitors are not yet available, homology models have been established, which helped to rationalize the binding modes and the design of new MCT inhibitors. In this review, we discuss the structures and functions of MCTs as well as recently reported small-molecule MCTs inhibitors. We assess the current development of MCT inhibitors and highlight possible directions for future development.
癌细胞通过无氧糖酵解代谢葡萄糖，细胞质中形成的乳酸盐是终产物。为了避免细胞间酸化，单羧酸转运蛋白（MCTs）将过量的乳酸盐和质子排出细胞，MCTs 在不同的恶性肿瘤中常过度表达。靶向 MCT 介导的乳酸盐/质子外排使 MCTs 成为一个有潜力的抗癌靶点。尽管还没有与抑制剂的人源 MCT 的 X 射线共晶结构，但已经建立了同源模型，这有助于合理化结合模式和设计新的 MCT 抑制剂。在这篇综述中，我们讨论了 MCTs 的结构和功能，以及最近报道的小分子 MCT 抑制剂。我们评估了 MCT 抑制剂的现状，并强调了未来发展的可能方向。
