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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Authors | Ke 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 |
Journal | Cell metabolism
(Cell Metab)
Vol. 30
Issue 6
Pg. 1107-1119.e8
(12 03 2019)
ISSN: 1932-7420 [Electronic] United States |
PMID | 31607564
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 Elsevier Inc. All rights reserved. |
Chemical References |
- ACTA2 protein, human
- Actins
- Anthracenes
- Enzyme Inhibitors
- HKB99
- Sulfonamides
- Phosphoglycerate Mutase
- phosphoglycerate mutase 1, human
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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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