Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China.
Bioorg Chem. 2021 Mar;108:104653. doi: 10.1016/j.bioorg.2021.104653. Epub 2021 Jan 19.
Pyruvate kinase M2 isoform (PKM2) plays a key role in cancer progression through both metabolic and non-metabolic functions, thus it is recognized as a potential target for cancer diagnosis and treatment. In this study, we discovered a sulfonamide-dithiocarbamate compound 8a as a novel PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8a analogs were designed and synthesized for screening as potent PKM2 activators. Among them, compound 8b (AC = 0.136 µM) and 8k (AC = 0.056 µM) showed higher PKM2 activation activities than positive control NZT (AC = 0.228 µM), and they (IC < 1 µM) exhibited more significant anti-proliferative activities against human tumor cell lines than NZT (IC > 10 µM). Especially, compound 8k inhibited the proliferation of multiple cancer cells, but showed little toxicity on normal cells. In addition, we found that compound 8k inhibit the colony formation of MCF7 cells. Western blot analysis demonstrated that 8k could reduce PKM2 nuclear localization and block the downstream signaling pathway of PKM2, resulting in suppression of tumor cell proliferation. Overall, compound 8k may be a promising candidate for further mechanistic investigation of PKM2 and cancer therapy.
丙酮酸激酶 M2 同工型（PKM2）通过代谢和非代谢功能在癌症进展中发挥关键作用，因此被认为是癌症诊断和治疗的潜在靶点。在这项研究中，我们从内部化合物库的随机筛选中发现了一种磺酰胺-二硫代氨基甲酸盐化合物 8a，它是一种新型的 PKM2 激活剂。然后，设计并合成了一系列先导化合物 8a 类似物进行筛选，以寻找更有效的 PKM2 激活剂。其中，化合物 8b（AC = 0.136 µM）和 8k（AC = 0.056 µM）显示出比阳性对照 NZT（AC = 0.228 µM）更高的 PKM2 激活活性，并且它们（IC < 1 µM）对人肿瘤细胞系的抗增殖活性比 NZT（IC > 10 µM）更显著。特别是，化合物 8k 抑制多种癌细胞的增殖，但对正常细胞的毒性较小。此外，我们发现化合物 8k 抑制 MCF7 细胞的集落形成。Western blot 分析表明，8k 可以减少 PKM2 的核定位并阻断 PKM2 的下游信号通路，从而抑制肿瘤细胞的增殖。总体而言，化合物 8k 可能是进一步研究 PKM2 和癌症治疗机制的有前途的候选药物。
