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

Autor:	Randolph JT; Abbvie Inc., North Chicago, Illinois 60064, United States., O'Connor MJ; Abbvie Inc., North Chicago, Illinois 60064, United States., Han F; Abbvie Inc., North Chicago, Illinois 60064, United States., Hutchins CW; Abbvie Inc., North Chicago, Illinois 60064, United States., Siu YA; Abbvie Inc., North Chicago, Illinois 60064, United States., Cho M; Calico Life Sciences LLC, South San Francisco, California 94080, United States., Zheng Y; Abbvie Inc., North Chicago, Illinois 60064, United States., Hickson JA; Abbvie Inc., North Chicago, Illinois 60064, United States., Markley JL; Abbvie Inc., North Chicago, Illinois 60064, United States., Manaves V; Abbvie Inc., North Chicago, Illinois 60064, United States., Algire M; Abbvie Inc., North Chicago, Illinois 60064, United States., Baker KA; Abbvie Inc., North Chicago, Illinois 60064, United States., Chapman AM; Abbvie Inc., North Chicago, Illinois 60064, United States., Gopalakrishnan SM; Abbvie Inc., North Chicago, Illinois 60064, United States., Panchal SC; Abbvie Inc., North Chicago, Illinois 60064, United States., Foster-Duke K; Abbvie Inc., North Chicago, Illinois 60064, United States., Stolarik DF; Abbvie Inc., North Chicago, Illinois 60064, United States., Kempf-Grote A; Abbvie Inc., North Chicago, Illinois 60064, United States., Dammeier D; Abbvie Inc., North Chicago, Illinois 60064, United States., Fossey S; Abbvie Inc., North Chicago, Illinois 60064, United States., Sun Q; Abbvie Inc., North Chicago, Illinois 60064, United States., Sun C; Abbvie Inc., North Chicago, Illinois 60064, United States., Shen Y; Abbvie Inc., North Chicago, Illinois 60064, United States., Dart MJ; Abbvie Inc., North Chicago, Illinois 60064, United States., Kati WM; Abbvie Inc., North Chicago, Illinois 60064, United States., Lai A; Abbvie Inc., North Chicago, Illinois 60064, United States., Firestone AJ; Calico Life Sciences LLC, South San Francisco, California 94080, United States., Kort ME; Abbvie Inc., North Chicago, Illinois 60064, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2023 Mar 23; Vol. 66 (6), pp. 3852-3865. Date of Electronic Publication: 2023 Mar 06.
DOI:	10.1021/acs.jmedchem.2c01415
Abstrakt:	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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu