Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.
Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.
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DOI：
10.1186/s13045-020-00979-y
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发表时间：
2020-10-21
影响因子：
28.5
通讯作者：
Ye K
中科院分区：
文献类型：
--
作者：
Lei K;Gu X;Alvarado AG;Du Y;Luo S;Ahn EH;Kang SS;Ji B;Liu X;Mao H;Fu H;Kornblum HI;Jin L;Li H;Ye K
胶质母细胞瘤（GBM）是一种普遍致命的肿瘤，经常过度表达或突变的表皮生长因子受体（EGFR）。NADPH醌氧化还原酶1（NQO 1）和谷胱甘肽-S-转移酶Pi 1（GSTP 1）通常在GBM中上调。NQO 1和GSTP 1减少活性氧（ROS）的形成，从而介导氧化应激并促进GBM细胞增殖。高通量筛选用于对具有EGFRvIII突变的GBM细胞具有选择性活性的试剂。共晶结构揭示了靶标识别的分子细节。药理学和基因敲低/过表达的方法被用来研究在体外和体内的氧化应激。我们鉴定了一种小分子抑制剂“MNPC”，其以高亲和力和选择性结合NQO 1和GSTP 1。MNPC抑制NQO 1和GST P1酶并诱导GBM中的细胞凋亡，特异性抑制携带EGFRvIII突变的细胞系和原代GBM的生长。MNPC和NQO 1之间的共晶体结构以及MNPC与GSTP 1的分子对接揭示了它结合活性位点并作为有效的双重抑制剂。用siRNA或MNPC灭活NQO 1和GSTP 1两者导致不平衡的氧化还原稳态，导致细胞凋亡并减轻体外和体内的癌症增殖。因此，MNPC，NQO 1和GSTP 1的双重抑制剂，提供了一种新的先导化合物，用于通过利用突变型EGFR产生的特异性脆弱性治疗GBM。
Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. We identified a small molecular inhibitor, “MNPC,” that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.
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影响因子：
4.7
作者：
Liu, L;Bäcklund, LM;Nilsson, BR;Grandér, D;Ichimura, K;Goike, HM;Collins, VP
通讯作者：
Collins, VP
DOI：
10.1107/s0907444904019158
发表时间：
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作者：
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