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. Epub 2019 Oct 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Animals
  • Anthracenes / pharmacology*
  • Anthracenes / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphoglycerate Mutase / antagonists & inhibitors*
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use

Substances

  • ACTA2 protein, human
  • Actins
  • Anthracenes
  • Enzyme Inhibitors
  • HKB99
  • Sulfonamides
  • Phosphoglycerate Mutase
  • phosphoglycerate mutase 1, human