pH regulators and their inhibitors in tumor microenvironment

• Published in: European journal of medicinal chemistry Vol. 267; p. 116170
• Main Authors: Liao, Senyi, Wu, Guang, Xie, Zhizhong, Lei, Xiaoyong, Yang, Xiaoyan, Huang, Sheng, Deng, Xiangping, Wang, Zhe, Tang, Guotao
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.03.2024
• Subjects: Carbonic anhydrase IX; Monocarboxylate transportors; Na+/H+ exchanger 1; pH regulators; Structure-activity relationship; Tumor microenvironment; Carbonic anhydrase IX; Tumor microenvironment; pH regulators; Structure-activity relationship; Monocarboxylate transportors; Na+/H+ exchanger 1; Na(+)/H(+) exchanger 1
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116170

As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets. [Display omitted] •Review of pH regulators related to tumor and their inhibitors.•Structure-activity relationship analysis.•The hypothesis of two interaction mode for MCT1 inhibitors.•Guide for future drug modification or drug design.