Cell metabolism, 2019-12, Vol.30 (6), p.1107-1119.e8
2019
Details
- Autor(en) / Beteiligte
- Titel
- A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer
- Ist Teil von
- Cell metabolism, 2019-12, Vol.30 (6), p.1107-1119.e8
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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. [Display omitted] •A PGAM1 allosteric inhibitor HKB99 is developed via structure-based optimization•HKB99 modulates PGAM1 both in its catalytic process and ACTA2 interaction•HKB99 suppresses NSCLC growth and metastasis through allosteric PGAM1 regulation•PGAM1 is a potential therapeutic target in NSCLC PGAM1 plays a critical role in cancer cell metabolism. Huang et al. discovered a novel PGAM1 inhibitor HKB99, which allosterically blocks the structure of PGAM1, impacting both its catalytic activity and ACTA2 interaction. HKB99 significantly inhibits NSCLC tumor growth and metastasis in vivo by impacting both PGAM1’s metabolic activity and nonmetabolic function.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1550-4131eISSN: 1932-7420DOI: 10.1016/j.cmet.2019.09.014Titel-ID: cdi_proquest_miscellaneous_2305477464
- Format
- –
- Schlagworte
- Actins - metabolism, allosteric inhibitor, Animals, Anthracenes - pharmacology, Anthracenes - therapeutic use, antitumor activity, 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, metastasis, Mice, Inbred BALB C, Mice, Nude, non-small-cell lung cancer, Phosphoglycerate Mutase - antagonists & inhibitors, phosphoglycerate mutase 1, Sulfonamides - pharmacology, Sulfonamides - therapeutic use