Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia

Jing Li, Shanshan Li, Jianshuang Guo, Qiuying Li, Jing Long, Cheng Ma, Yahui Ding, Chunli Yan, Liangwei Li, Zhigang Wu, He Zhu, Keqin Kathy LI, Liuqing Wen, Quan Zhang, Qingqing Xue, Caili Zhao, Ning Liu, Ivaylo Ivanov, Ming Luo, Rimo Xi, Haibo Long, Peng George Wang, Yue Chen

Index: 10.1021/acs.jmedchem.8b00241

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Abstract

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 the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia and shows encouraging treatment results, our discovery may provide valuable pharmacological mechanism for the clinical treatment and benefit the development of new anti-cancer agents.