New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Pyruvate kinase M2 (PKM2) is a key protein responsible for cancer's Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line. (C) 2015 Elsevier Ltd. All rights reserved.National Natural Science Funds of China [21172011, 81372491, 81430056, 31420103905, 81321003]; 111 Project [B07001]SCI(E)PubMedARTICLElirt@bjmu.edu.cn; yinyuxin@hsc.pku.edu.cn154815-48232