A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer
A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer
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磷酸甘油酸变位酶 1 的新型变构抑制剂可抑制非小细胞肺癌的生长和转移
DOI：
10.1016/j.cmet.2019.09.014
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发表时间：
2019-12-03
期刊：
影响因子：
29
通讯作者：
Shen, Ying
中科院分区：
文献类型：
--
作者：
Huang, Ke;Liang, Qian;Shen, Ying
磷酸甘油酸突变酶1 （PGAM1）通过其代谢活性和与α -平滑肌肌动蛋白（ACTA2）等其他蛋白的相互作用，在癌症代谢和肿瘤进展中发挥关键作用。变构调节被认为是发现一种高选择性和有效的靶向PGAM1抑制剂的创新策略。在这里，我们通过结构优化鉴定了一种新的PGAM1变构抑制剂HKB99。HKB99在催化过程和PGAM1- acta2相互作用中变构阻止PGAM1的构象变化。在非小细胞肺癌（NSCLC）中，HKB99抑制肿瘤生长和转移，克服厄洛替尼耐药。机制上，HKB99增强了氧化应激，改变了多种信号通路，包括JNK/c-Jun的激活和AKT和ERK的抑制。总的来说，该研究强调了PGAM1作为非小细胞肺癌治疗靶点的潜力，并揭示了HKB99通过变抗调节抑制PGAM1代谢活性和非代谢功能的独特机制。
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.