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

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.
AuthorsKe Huang, Qian Liang, Ye Zhou, Lu-Lu Jiang, Wei-Ming Gu, Ming-Yu Luo, Ya-Bin Tang, Yang Wang, Wei Lu, Min Huang, Sheng-Zhe Zhang, Guang-Lei Zhuang, Qing Dai, Qian-Cheng Shen, Jian Zhang, Hui-Min Lei, Liang Zhu, De-Yong Ye, Hong-Zhuan Chen, Lu Zhou, Ying Shen
JournalCell metabolism (Cell Metab) Vol. 30 Issue 6 Pg. 1107-1119.e8 (12 03 2019) ISSN: 1932-7420 [Electronic] United States
PMID31607564 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2019 Elsevier Inc. All rights reserved.
Chemical References
  • ACTA2 protein, human
  • Actins
  • Anthracenes
  • Enzyme Inhibitors
  • HKB99
  • Sulfonamides
  • Phosphoglycerate Mutase
  • phosphoglycerate mutase 1, human
Topics
  • Actins (metabolism)
  • Animals
  • Anthracenes (pharmacology, therapeutic use)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
  • Cell Line, Tumor
  • Cell Movement (drug effects)
  • Cell Proliferation (drug effects)
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • Female
  • Humans
  • Lung Neoplasms (drug therapy, metabolism)
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphoglycerate Mutase (antagonists & inhibitors)
  • Sulfonamides (pharmacology, therapeutic use)

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