2019年10月10日，上海交通大学医学院沈瑛副研究员、复旦大学药学院周璐副教授和上海中医药大学陈红专教授等研究人员合作在《细胞—代谢》杂志在线发表论文，报道了一个能够抑制非小细胞肺癌的生长和转移的磷酸甘油酸突变酶1（PGAM1）变构抑制剂。

研究人员通过基于结构的优化确定了一种新型PGAM1变构抑制剂HKB99。HKB99在催化过程和PGAM1与α平滑肌肌动蛋白ACTA2相互作用过程中变构地阻断PGAM1的构象变化。HKB99抑制了非小细胞肺癌的肿瘤生长和转移并克服了埃洛替尼耐药性。从机理上讲，HKB99增强了氧化应激并改变了多种信号传导途径，包括JNK/c-Jun的激活以及AKT和ERK的抑制。因此，这项研究强调了PGAM1作为非小细胞肺癌治疗靶点的潜力，并揭示了HKB99通过变构调节抑制PGAM1的代谢活性和非代谢功能的独特机制。

据了解，PGAM1通过其代谢活性以及与其他蛋白质（例如ACTA2的相互作用，在癌症代谢和肿瘤进展中起关键作用。变构调节被认为是发现针对PGAM1的高选择性和有效抑制剂的创新策略。

附：英文原文

Title: A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer

Author: 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

Issue&Volume: 10 October 2019

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.

DOI: 10.1016/j.cmet.2019.09.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30517-0