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A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer

文献类型：期刊论文

作者Huang, Ke3; Liang, Qian4,5; Zhou, Ye4,5; Jiang, Lu-lu3; Gu, Wei-ming4,5; Luo, Ming-yu4,5; Tang, Ya-bin4,5; Wang, Yang4,5; Lu, Wei6,7,8; Huang, Min9
刊名CELL METABOLISM
出版日期2019-12-03
卷号30期号:6页码:1107-+
ISSN号1550-4131
DOI10.1016/j.cmet.2019.09.014
通讯作者Chen, Hong-zhuan(hongzhuan_chen@hotmail.com) ; Zhou, Lu(zhoulu@fudan.edu.cn) ; Shen, Ying(yshen0510@sjtu.edu.cn)
英文摘要Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like alpha-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.
WOS关键词EGFR MUTATION ; RESISTANCE ; APOPTOSIS ; TARGET ; MAPK ; BIOSYNTHESIS ; METABOLISM ; SURVIVAL ; THERAPY ; ACID
资助项目National Natural Science Foundation of China[81773748] ; National Natural Science Foundation of China[81473232] ; National Natural Science Foundation of China[21472026] ; National Natural Science Foundation of China[21877014] ; National Natural Science Foundation of China[81872841] ; National Natural Science Foundation of China[81573018] ; National Natural Science Foundation of China[91853206] ; Construction Project of High Level Local Universities in Shanghai and Pharmacy[XD18011] ; Interdisciplinary Program of Shanghai Jiao Tong University[YG2017MS82]
WOS研究方向Cell Biology ; Endocrinology & Metabolism
语种英语
出版者CELL PRESS
WOS记录号WOS:000500800300011
源URL[http://119.78.100.183/handle/2S10ELR8/282147]  
专题新药研究国家重点实验室
通讯作者Chen, Hong-zhuan; Zhou, Lu; Shen, Ying
作者单位1.Shanghai Jiao Tong Univ, Sch Med, Med Bioinformat Ctr, State Key Lab Oncogenes & Related Genes, Shanghai 200025, Peoples R China
2.Shanghai Univ Tradit Chinese Med, Shuguang Hosp, Inst Interdisciplinary Integrat Biomed Res, Shanghai 201203, Peoples R China
3.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Med, Dept Pharmacol & Chem Biol, Shanghai 200025, Peoples R China
5.Shanghai Collaborat Innovat Ctr Translat Med, Shanghai 200025, Peoples R China
6.Fudan Univ, Sch Pharm, Minist Educ, Key Lab Smart Drug Delivery, Shanghai 201203, Peoples R China
7.Fudan Univ, Sch Pharm, State Key Lab Mol Engn Polymers, Shanghai 201203, Peoples R China
8.Fudan Univ, Minhang Hosp, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
10.Shanghai Jiao Tong Univ, Sch Med, State Key Lab Oncogenes & Related Genes, Renji Hosp,Dept Obstet & Gynecol, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Huang, Ke,Liang, Qian,Zhou, Ye,et al. A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer[J]. CELL METABOLISM,2019,30(6):1107-+.
APA Huang, Ke.,Liang, Qian.,Zhou, Ye.,Jiang, Lu-lu.,Gu, Wei-ming.,...&Shen, Ying.(2019).A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.CELL METABOLISM,30(6),1107-+.
MLA Huang, Ke,et al."A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer".CELL METABOLISM 30.6(2019):1107-+.

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来源：上海药物研究所

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