Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

Journal of Hematology & Oncology

Keqiang Ye¹  Eun Hee Ahn¹  Shilin Luo¹  Xia Liu¹  Seong Su Kang¹  Kecheng Lei²  Haian Fu³  Yuhong Du³  Hui Mao⁴  Bing Ji⁴  Harley I. Kornblum⁵  Alvaro G. Alvarado⁵  Lingjing Jin⁶  Xiaoxia Gu⁷  Hua Li⁸ 

[1] Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA;Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, People’s Republic of China;Department of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Atlanta, USA;Department of Radiology and Imaging Sciences, Emory University School of Medicine, 30322, Atlanta, GA, USA;Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA;Neurotoxin Research Center of Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Neurological Department of Tongji Hospital, Tongji University School of Medicine, 200065, Shanghai, People’s Republic of China;School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, People’s Republic of China;School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, People’s Republic of China;Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China;

关键词: Oxidative stress;    NQO1;    GSTP1;    GBM;    Small molecular inhibitor;   

DOI  :  10.1186/s13045-020-00979-y

来源: Springer

【 摘 要 】

BackgroundGlioblastoma (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.MethodsHigh-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.ResultsWe 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.ConclusionsThus, 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.

【 授权许可】

CC BY