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

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

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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