A catalase inhibitor: Targeting the NADPH-binding site for castration-resistant prostate cancer therapy
Ya Ya Cao,
Yuan Yuan Chen,
Ming Shu Wang,
Jing Jing Tong,
Meng Xu,
Chi Zhao,
Hong Yan Lin,
Long Can Mei,
Jin Dong,
Wen Lin Zhang,
Yu Xuan Qin,
Wei Huang,
Dan Zhang,
Guang Fu Yang
Affiliations
Ya Ya Cao
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Yuan Yuan Chen
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Ming Shu Wang
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Jing Jing Tong
School of Life Sciences, Central China Normal University, Wuhan, 430079, PR China
Meng Xu
School of Life Sciences, Central China Normal University, Wuhan, 430079, PR China
Chi Zhao
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Hong Yan Lin
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Long Can Mei
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Jin Dong
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Wen Lin Zhang
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Yu Xuan Qin
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Wei Huang
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China
Dan Zhang
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China; Corresponding author.
Guang Fu Yang
National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China; Corresponding author.
Catalase (CAT) is an important antioxidant enzyme that breaks down H2O2 into water and oxygen. Inhibitor-modulating CAT activity in cancer cells is emerging as a potential anticancer strategy. However, the discovery of CAT inhibitors towards the heme active center located at the bottom of long and narrow channel has made little progress. Therefore, targeting new binding site is of great importance for the development of efficient CAT inhibitors. Here, the first NADPH-binding site inhibitor of CAT, BT-Br, was designed and synthesized successfully. The cocrystal structure of BT-Br-bound CAT complex was determined with a resolution of 2.2 Å (PDB ID:8HID), which showed clearly that BT-Br bound at the NADPH-binding site. Furthermore, BT-Br was demonstrated to induce ferroptosis in castration-resistant prostate cancer (CRPC) DU145 cells and eventually reduce CRPC tumors in vivo effectively. The work indicates that CAT has potential as a novel target for CRPC therapy based on ferroptosis inducing.
