Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC₅₀ values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies.

丙酮酸激酶 M2 同工型 (PKM2) 是负责癌细胞有氧糖酵解的关键蛋白质。 PKM2 的激活可能会改变癌细胞的异常代谢。在这项研究中，我们从内部化合物库的随机筛选中发现了 4-羟基-噻唑烷-2-硫酮化合物2作为新型 PKM2 激活剂。然后设计并合成了一系列新型4-羟基-噻唑烷-2-硫酮衍生物，用于筛选有效的 PKM2 激活剂。其中，一些化合物表现出比先导化合物2更高的PKM2激活活性，并且在纳摩尔浓度下对人类癌细胞系表现出显着的抗增殖活性。化合物5w被认为是最有效的抗肿瘤药物，对H1299、HCT116、Hela和PC3细胞系表现出优异的抗增殖作用，IC ₅₀值为0.46 μM至0.81 μM。与癌细胞相比， 5w在非肿瘤细胞系 HELF 中也显示出较低的细胞毒性。此外，初步药理学研究表明， 5w可使 HCT116 细胞系的细胞周期停滞在 G2/M 期。通过对接研究合理化了化合物5t的最佳 PKM2 激活。