A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer
Authors: Yang Wang
Hong-Zhuan Chen
Lu Zhou
Liang Zhu
Min Huang
Sheng-Zhe Zhang
Qian Liang
Qian-Cheng Shen
Jian Zhang
Lu-Lu Jiang
Ke Huang
Wei-Ming Gu
Ya-Bin Tang
Wei Lu
Hui-Min Lei
Ying Shen
De-Yong Ye
Qing Dai
Ye Zhou
Ming-Yu Luo
Guang-Lei Zhuang
Journal: Cell Metabolism (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: allosteric inhibitor; antitumor activity; metastasis; non-small-cell lung cancer; phosphoglycerate mutase 1.
Affiliations: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China., Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China., Key Laboratory of Smart Drug Delivery, Ministry of Education & State Key Laboratory of Molecular Engineering of Polymers, School of Pharmacy & Minhang Hospital, Fudan University, Shanghai 201203, China., Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China., State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China., Department of Chemistry, University of Chicago, Chicago, IL 60637, USA., State Key Laboratory of Oncogenes and Related Genes, Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China., Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: ., Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: ., Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Shanghai Collaborative Innovation Center for Translational Medicine, Shanghai 200025, China. Electronic address: .

Abstract:  Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like Œ±-smooth muscle actin (ACTA2). Allosteric regulation is considered to be an innovative strategy to discover a highly selective and potent inhibitor targeting PGAM1. Here, we identified a novel PGAM1 allosteric inhibitor, HKB99, via structure-based optimization. HKB99 acted to allosterically block conformational change of PGAM1 during catalytic process and PGAM1-ACTA2 interaction. HKB99 suppressed tumor growth and metastasis and overcame erlotinib resistance in non-small-cell lung cancer (NSCLC). Mechanistically, HKB99 enhanced the oxidative stress and altered multiple signaling pathways including the activation of JNK/c-Jun and suppression of AKT and ERK. Collectively, the study highlights the potential of PGAM1 as a therapeutic target in NSCLC and reveals a distinct mechanism by which HKB99 inhibits both metabolic activity and nonmetabolic function of PGAM1 by allosteric regulation. 

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