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  3. A catalase inhibitor: Targeting the NADPH-binding site for castration-resistant prostate cancer therapy

A catalase inhibitor: Targeting the NADPH-binding site for castration-resistant prostate cancer therapy

  • Redox Biol. 2023 Jul:63:102751. doi: 10.1016/j.redox.2023.102751.
Ya Ya Cao 1,  Yuan Yuan Chen 1,  Ming Shu Wang 1,  Jing Jing Tong 2,  Meng Xu 2,  Chi Zhao 1,  Hong Yan Lin 1,  Long Can Mei 1,  Jin Dong 1,  Wen Lin Zhang 1,  Yu Xuan Qin 1,  Wei Huang 1,  Dan Zhang 3,  Guang Fu Yang 4
Affiliations

Affiliations

  • 1 National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China.
  • 2 School of Life Sciences, Central China Normal University, Wuhan, 430079, PR China.
  • 3 National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China. Electronic address: [email protected].
  • 4 National Key Laboratory of Green Pesticide, International Joint Research Center for Intelligent Biosensor Technology and Health, Central China Normal University, Wuhan, 430079, PR China. Electronic address: [email protected].
PMID: 37216701 DOI: 10.1016/j.redox.2023.102751
Abstract

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.

Keywords

Castration-resistant prostate cancer; Catalase inhibitors; Ferroptosis; NADPH-Binding site.

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