title: Off-target immune cell toxicity caused by AG-012986, a pan-CDK inhibitor, is associated with inhibition of p38 MAPK phosphorylation.
abstract: AG-012986 is a pan-CDK (cyclin-dependent kinase) inhibitor that has in vitro and in vivo antitumor properties but was stopped in development due in part to rapid bone-marrow-independent white blood cell toxicity in preclinical studies and the potential for acute and delayed immunosuppression in humans. Because peripheral lymphocytes are largely nonproliferating, it was hypothesized the toxicity of AG-012986 was due to an off-target mechanism and not driven by the intended pharmacology. We show the toxicity mechanism in primary human immune cells is caspase driven. T-cells treated with AG-012986 and acutely stimulated through the T-cell receptor exhibited decreased toxicity while still maintaining cell division inhibition. This indicated that the pharmacology of AG-012986 functioned as expected but the toxicity had now been decoupled through activation. Induced phosphorylation of p38 and IL-2 production was impaired with AG-012986. Thus, AG-012986 could cause apoptosis of T-cells by targeting upstream kinases in the p38 Mitogen-activated protein kinase (MAPK) pathway and impairing cellular survival.
authors.affiliation: Pfizer Global Research and Development, Drug Safety Department, 10646 Science Center Drive, San Diego, CA 92121, USA. dong.lee2@pfizer.com
authors.forename: Dong U
authors.initials: DU
authors.lastname: Lee
authors.forename: Bart
authors.initials: B
authors.lastname: Jessen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003603:Cytotoxins / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C512484:AG-012986; D001549:Benzamides; D003603:Cytotoxins; D007376:Interleukin-2; D013844:Thiazoles; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019311:Staurosporine