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

  • J Med Chem. 2023 Mar 23;66(6):3852-3865. doi: 10.1021/acs.jmedchem.2c01415.
John T Randolph  1 ,  Matthew J O'Connor  1 ,  Fei Han  1 ,  Charles W Hutchins  1 ,  Y Amy Siu  1 ,  Min Cho  2 ,  Yunan Zheng  1 ,  Jonathan A Hickson  1 ,  Jana L Markley  1 ,  Vlasios Manaves  1 ,  Mikkel Algire  1 ,  Kenton A Baker  1 ,  Alex M Chapman  1 ,  Sujatha M Gopalakrishnan  1 ,  Sanjay C Panchal  1 ,  Kelly Foster-Duke  1 ,  DeAnne F Stolarik  1 ,  Anita Kempf-Grote  1 ,  Darby Dammeier  1 ,  Stacey Fossey  1 ,  Qi Sun  1 ,  Chaohong Sun  1 ,  Yu Shen  1 ,  Michael J Dart  1 ,  Warren M Kati  1 ,  Albert Lai  1 ,  Ari J Firestone  2 ,  Michael E Kort  1
Affiliations
  • 1. Abbvie Inc., North Chicago, Illinois 60064, United States.
  • 2. Calico Life Sciences LLC, South San Francisco, California 94080, United States.
PMID: 36877935 DOI: 10.1021/acs.jmedchem.2c01415
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 (t1/2 > 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.

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