Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors

Area of Science:

• Neuroscience
• Cell Biology
• Pharmacology

Background:

• Ferroptosis is a novel cell death pathway implicated in various human diseases.
• Developing ferroptosis inhibitors is a promising therapeutic strategy for ferroptosis-related conditions.

Purpose of the Study:

• To screen for ferroptosis inhibitors using an FDA-approved drug library.
• To identify and optimize novel ferroptosis inhibitors for potential therapeutic applications.

Main Methods:

• Screening of 1160 FDA-approved molecules in RSL3-induced HT22 mouse hippocampal neuronal cells.
• Structure-activity relationship (SAR) analysis and synthesis of 41 novel olanzapine derivatives.
• Evaluation of ferroptosis inhibitory activity (EC50) and cytotoxicity (CC50).

Main Results:

• Olanzapine demonstrated potent ferroptosis inhibitory activity (EC50 = 1.18 μM).
• Derivative 36 exhibited a 16-fold improvement in ferroptosis inhibition (EC50 = 0.074 μM) with low cytotoxicity (CC50 = 18.8 μM).
• Compound 36's mechanism involves specific ferroptosis inhibition via antioxidative properties.

Conclusions:

• Olanzapine effectively protects against RSL3-induced ferroptosis in HT22 cells.
• Compound 36, with its nanomolar inhibitory activity and low toxicity, represents a promising candidate for developing drugs targeting ferroptosis-related neurological diseases.