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

  • Cell Metab. 2019 Dec 3;30(6):1107-1119.e8. doi: 10.1016/j.cmet.2019.09.014.
Ke Huang  1 ,  Qian Liang  2 ,  Ye Zhou  2 ,  Lu-Lu Jiang  1 ,  Wei-Ming Gu  2 ,  Ming-Yu Luo  2 ,  Ya-Bin Tang  2 ,  Yang Wang  2 ,  Wei Lu  3 ,  Min Huang  4 ,  Sheng-Zhe Zhang  5 ,  Guang-Lei Zhuang  5 ,  Qing Dai  6 ,  Qian-Cheng Shen  7 ,  Jian Zhang  7 ,  Hui-Min Lei  2 ,  Liang Zhu  2 ,  De-Yong Ye  1 ,  Hong-Zhuan Chen  8 ,  Lu Zhou  9 ,  Ying Shen  10
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2. 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.
  • 3. 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.
  • 4. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5. 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.
  • 6. Department of Chemistry, University of Chicago, Chicago, IL 60637, USA.
  • 7. State Key Laboratory of Oncogenes and Related Genes, Medicinal Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
  • 8. Institute of Interdisciplinary Integrative Biomedical Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 9. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: [email protected].
  • 10. 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: [email protected].
PMID: 31607564 DOI: 10.1016/j.cmet.2019.09.014
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 α-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.

Keywords
allosteric inhibitor; antitumor activity; metastasis; non-small-cell lung cancer; phosphoglycerate mutase 1.
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