A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.
Cell Metab
; 30(6): 1107-1119.e8, 2019 12 03.
Article
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| MEDLINE
| ID: mdl-31607564
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.
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Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Actinas
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Carcinoma de Pulmón de Células no Pequeñas
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Fosfoglicerato Mutasa
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Inhibidores Enzimáticos
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Neoplasias Pulmonares
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Idioma:
En
Revista:
Cell Metab
Asunto de la revista:
METABOLISMO
Año:
2019
Tipo del documento:
Article