State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Haihe Education Park, 38 Tongyan Road , Tianjin 300350 , China.
Center for Diagnostics and Therapeutics, Department of Chemistry , Georgia State University , Atlanta , Georgia 30303 , United States.
J Med Chem. 2018 May 10;61(9):4155-4164. doi: 10.1021/acs.jmedchem.8b00241. Epub 2018 Apr 29.
Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (PKM2), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.
癌细胞的代谢重编程对于肿瘤发生是至关重要的，其中丙酮酸激酶 M2（PKM2）作为丙酮酸激酶的低活性同工酶，发挥着关键作用。在此，我们描述了一种天然产物衍生的米利醇（MCL）的鉴定，它通过与 PKM1 中不含有的半胱氨酸 424（C424）残基的共价结合，选择性地激活 PKM2。这种相互作用促进了更多的四聚体形成，抑制了赖氨酸 433（K433）乙酰化，并影响了 PKM2 向核内的易位。此外，具有与 MCL 相似性质的前药二甲氨基米利醇（DMAMCL）在斑马鱼异种移植模型中显著抑制白血病细胞的生长和肿瘤发生。基于敲低 PKM2 表达的细胞测定验证了 MCL 的作用依赖于 PKM2 的表达。DMAMCL 目前正在澳大利亚进行临床试验。我们的发现可能为临床治疗提供了有价值的药理学机制，并有助于开发新的抗癌药物。
