Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury

Exaggerated or inappropriate signaling by the platelet-derived growth facto r receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identif ied as potent antagonists of the PDGFR by screening chemical libraries. An optimized analog, CT52923, was shown to be an ATP-competitive inhibitor tha t exhibited remarkable specificity when tested against other kinases, inclu ding all members of the closely related PDGFR family. The PDGFRs and stem c ell factor receptor were inhibited with an IC50 of 100 to 200 nM, while 45- to >200-fold higher concentrations of CT52923 were required to inhibit fms -like tyrosine kinase-3 and colony-stimulating factor-1 receptor, respectiv ely. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/ threonine kinases, or members of the mitogen-activated protein kinase pathw ay were not significantly inhibited at 100- to 1000-fold higher concentrati ons. In addition, this compound also demonstrated specificity for inhibitio n of cellular responses. Platelet-derived growth factor-induced smooth musc le cell migration or fibroblast proliferation was found to be blocked by CT 52923 with an IC50 of 64 and 280 nM, respectively, whereas 50- to 100-fold higher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDG FR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral admini stration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viab le strategy for the prevention of clinical restenosis or the treatment of o ther human diseases involving PDGFR signaling.