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A Novel Allosteric Inhibitor of Phosphoglycerate Mutase 1 Suppresses Growth and Metastasis of Non-Small-Cell Lung Cancer.
Cell Metabolism ( IF 29.0 ) Pub Date : 2019-10-10 , DOI: 10.1016/j.cmet.2019.09.014 Ke Huang 1 , Qian Liang 2 , Ye Zhou 2 , Lu-Lu Jiang 1 , Wei-Ming Gu 2 , Ming-Yu Luo 2 , Ya-Bin Tang 2 , Yang Wang 2 , Wei Lu 3 , Min Huang 4 , Sheng-Zhe Zhang 5 , Guang-Lei Zhuang 5 , Qing Dai 6 , Qian-Cheng Shen 7 , Jian Zhang 7 , Hui-Min Lei 2 , Liang Zhu 2 , De-Yong Ye 1 , Hong-Zhuan Chen 8 , Lu Zhou 1 , Ying Shen 2
Cell Metabolism ( IF 29.0 ) Pub Date : 2019-10-10 , DOI: 10.1016/j.cmet.2019.09.014 Ke Huang 1 , Qian Liang 2 , Ye Zhou 2 , Lu-Lu Jiang 1 , Wei-Ming Gu 2 , Ming-Yu Luo 2 , Ya-Bin Tang 2 , Yang Wang 2 , Wei Lu 3 , Min Huang 4 , Sheng-Zhe Zhang 5 , Guang-Lei Zhuang 5 , Qing Dai 6 , Qian-Cheng Shen 7 , Jian Zhang 7 , Hui-Min Lei 2 , Liang Zhu 2 , De-Yong Ye 1 , Hong-Zhuan Chen 8 , Lu Zhou 1 , Ying Shen 2
Affiliation
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.
中文翻译:
磷酸甘油酸酯突变酶1的新型变构抑制剂抑制非小细胞肺癌的生长和转移。
磷酸甘油酸突变酶1(PGAM1)通过其代谢活性以及与其他蛋白质(例如α平滑肌肌动蛋白(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的高度选择性和有效抑制剂的创新策略。在这里,我们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-ACTA2相互作用过程中能变构地阻断PGAM1的构象变化。HKB99抑制了非小细胞肺癌(NSCLC)中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。总的来说,
更新日期:2019-11-09
中文翻译:
磷酸甘油酸酯突变酶1的新型变构抑制剂抑制非小细胞肺癌的生长和转移。
磷酸甘油酸突变酶1(PGAM1)通过其代谢活性以及与其他蛋白质(例如α平滑肌肌动蛋白(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的高度选择性和有效抑制剂的创新策略。在这里,我们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-ACTA2相互作用过程中能变构地阻断PGAM1的构象变化。HKB99抑制了非小细胞肺癌(NSCLC)中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。总的来说,