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

Area of Science:

• Biochemistry
• Enzymology
• Medicinal Chemistry

Background:

• Catalase (CAT) is a crucial antioxidant enzyme that metabolizes hydrogen peroxide.
• Modulating CAT activity presents a potential anticancer strategy, but targeting its heme active site has yielded limited success.
• Identifying novel binding sites is essential for developing effective CAT inhibitors.

Purpose of the Study:

• To design and synthesize the first inhibitor targeting the NADPH-binding site of CAT.
• To investigate the therapeutic potential of this novel inhibitor in castration-resistant prostate cancer (CRPC).

Main Methods:

• Design and synthesis of a novel CAT inhibitor, BT-Br.
• Determination of the co-crystal structure of the BT-Br-bound CAT complex (PDB ID: 8HID).
• In vitro assessment of BT-Br's ability to induce ferroptosis in DU145 cells and in vivo efficacy in reducing CRPC tumors.

Main Results:

• Successfully designed and synthesized BT-Br, the first NADPH-binding site inhibitor for CAT.
• The co-crystal structure confirmed BT-Br binding to the NADPH site.
• BT-Br effectively induced ferroptosis in CRPC DU145 cells and reduced tumor growth in vivo.

Conclusions:

• The NADPH-binding site of CAT is a viable target for inhibitor development.
• BT-Br demonstrates significant potential as a therapeutic agent for CRPC by inducing ferroptosis.
• CAT represents a novel therapeutic target for CRPC treatment via ferroptosis induction.