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>
John T. Randolph, Matthew J. O’Connor, Fei Han, Charles W. Hutchins, Y. Amy Siu, Min Cho, Yunan Zheng, Jonathan A. Hickson, Jana L. Markley, Vlasios Manaves, Mikkel A. Algire, Kenton A. Baker, Alex M. Chapman, Sujatha M. Gopalakrishnan, Sanjay C. Panchal, Kelly D. Foster-Duke, DeAnne Stolarik, Anita J. Kempf-Grote, Darby Dammeier, Stacey Fossey, Qi Sun, Chaohong Sun, Yu Shen, Michael J. Dart, Warren M. Kati, Albert Lai, Ari J. Firestone, Michael E. Kort
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 24, a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability ( t 1/2 > 5 h in mouse plasma). The bioavailability of 24 provided efficacious plasma drug concentrations with IP dosing, thus enabling in vivo studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of 24 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.