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

• Type of Material: Article
• Authors: Kecheng Lei, Emory University; Xiaoxia Gu, Huazhong University of Science & Technology; Alvaro G. Alvarado, University of California Los Angeles; Yuhong Du, Emory University; Shilin Luo, Emory University; Eun Hee Ahn, Emory University; Seong Kang, Emory University; Bing Ji, Emory University; Xia Liu, Emory University; Hui Mao, Emory University; Haian Fu, Emory University; Harley I. Kornblum, University of California Los Angeles; Lingjing Jin, Tongji University; Hua Li, Huazhong University of Science & Technology; Keqiang Ye, Emory University
• Language: English
• Date: 2020-10-21
• Publisher: BMC
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13045-020-00979-y
• Title of Journal or Parent Work: JOURNAL OF HEMATOLOGY & ONCOLOGY
• Volume: 13
• Issue: 1
• Start Page: 141
• End Page: 141
• Grant/Funding Information: This work is funded in part with Federal funds from National Cancer Institute (NCI), National Institutes of Health (NIH) (RO1 CA186918) to K.Y; The University of California Presidents Postdoctoral Fellowship (AGA), and the UCLA SPORE in Brain Cancer NCI: P50 CA211015-01A1 (HIK). Dr. Kecheng Lei was supported by grants from China Postdoctoral Science Foundation (2018M632168).
• Keywords: EGFR; Small molecular inhibitor; QUINONE OXIDOREDUCTASE-1; Life Sciences & Biomedicine; GLUTATHIONE-S-TRANSFERASE; Science & Technology; TARGETED THERAPY; Hematology; CELL; GSTP1; GENE-EXPRESSION; NQO1; TUMOR-SUPPRESSOR PTEN; Oxidative stress; INACTIVATION; Oncology; RESISTANCE; GBM; GROWTH
• Research Categories: Biology, Cell; Biology, Genetics; Health Sciences, Oncology

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.