期刊
CELL METABOLISM
卷 30, 期 6, 页码 1107-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.09.014
关键词
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资金
- National Natural Science Foundation of China [81773748, 81473232, 21472026, 21877014, 81872841, 81573018, 91853206]
- Construction Project of High Level Local Universities in Shanghai and Pharmacy [XD18011]
- Interdisciplinary Program of Shanghai Jiao Tong University [YG2017MS82]
Phosphoglycerate mutase 1 (PGAM1) plays a pivotal role in cancer metabolism and tumor progression via its metabolic activity and interaction with other proteins like alpha-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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