Abstract 254: Discovery of dual inhibitors of NQO1 and GSTP1 for malignant glioblastoma treatment

Abstract

Abstract Glioblastoma (GBM) is a highly aggressive form of neoplasia due to its frequently overexpressed or mutant epidermal growth factor receptor (EGFR). NADPH quinone Oxydoreductase1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 are enzymes with dual roles that decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and GBM cell proliferation. To search for a small molecule that blocks the malignant cancer proliferation, we conducted a high-throughput Screening (HTS) and identified a small molecule inhibitor (5-methyl-N-(nitro-1,3-thiazol-2-yl)-3-phenylisoxazole-4-carboxamide) as “HIT” that binds to both NQO1 and GSTP1 with high affinity and selectivity. The “HIT” blocks NQO1 and GSTP1 enzyme activity and mediates apoptosis in GBM via caspase activation. Inactivation of NQO1 and GSTP1 with siRNA or HIT resulted in imbalanced redox homeostasis, leading to mitigated cancer cell proliferation in vitro and in vivo. Thus, optimization of “HIT”, the dual NQO1 and GSTP1 inhibitor, may provide a novel strategy to antagonizing GBM. Citation Format: Kecheng Lei, Shilin Luo, Lingjing Jin, Keqiang Ye. Discovery of dual inhibitors of NQO1 and GSTP1 for malignant glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 254.