Discovery of a Potent Chloroacetamide GPX4 Inhibitor with Bioavailability to Enable Target Engagement in Mice, a Potential Tool Compound for Inducing Ferroptosis <i>In Vivo</i>

Abstract

Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified <b>24</b>, a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability (<i>t</i>_1/2 > 5 h in mouse plasma). The bioavailability of <b>24</b> provided efficacious plasma drug concentrations with IP dosing, thus enabling <i>in vivo</i> studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of <b>24</b> up to 50 mg/kg were tolerated for 20 days but had no effect on tumor growth, although partial target engagement was observed in tumor homogenate.