Discovery of a Potent Chloroacetamide GPX4 Inhibitor with Bioavailability to Enable Target Engagement in Mice, a...

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Glutathione peroxidase 4 (GPX4) inhibitors show promise for cancer therapy by inducing ferroptosis, a non-apoptotic cell death pathway.
• Developing stable and bioavailable GPX4 inhibitors is crucial for effective in vivo cancer treatment.

Purpose of the Study:

• To identify and characterize a novel, plasma-stable analog of the GPX4 inhibitor RSL3.
• To evaluate the in vivo tolerability, pharmacokinetics, and efficacy of the novel compound in a mouse tumor model.

Main Methods:

• Synthesis and characterization of compound 24, a structural analog of RSL3.
• Assessment of plasma stability and pharmacokinetic properties of compound 24 in mice.
• In vivo efficacy study in a GPX4-sensitive mouse tumor model, including tolerability and target engagement assessment.

Main Results:

• Compound 24 demonstrated significantly improved plasma stability (t1/2 > 5 h) compared to RSL3.
• Intraperitoneal (IP) dosing of compound 24 achieved efficacious plasma concentrations in mice.
• Doses up to 50 mg/kg were well-tolerated for 20 days in mice but did not inhibit tumor growth, despite partial GPX4 target engagement in tumor homogenates.

Conclusions:

• Compound 24 is a stable and bioavailable GPX4 inhibitor with potential for further development.
• Further optimization is required to achieve therapeutic efficacy in vivo, as compound 24 alone did not reduce tumor growth.
• The study highlights the challenges in translating GPX4 inhibition into effective cancer therapy despite promising preclinical properties.