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Titolo:
Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury
Autore:
Yu, JC; Lokker, NA; Hollenbach, S; Apatira, M; Li, J; Betz, A; Sedlock, D; Oda, S; Nomoto, Y; Matsuno, K; Ide, SI; Tsukuda, E; Giese, NA;
Indirizzi:
COR Therapeut Inc, S San Francisco, CA 94080 USA COR Therapeut Inc S San Francisco CA USA 94080 an Francisco, CA 94080 USA Kyowa Hakko Kogyo Co Ltd, Pharmaceut Res Inst, Shizuoka, Japan Kyowa HakkoKogyo Co Ltd Shizuoka Japan aceut Res Inst, Shizuoka, Japan
Titolo Testata:
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
fascicolo: 3, volume: 298, anno: 2001,
pagine: 1172 - 1178
SICI:
0022-3565(200109)298:3<1172:EOTNSP>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
TYROSINE KINASE INHIBITOR; PDGF-RECEPTOR; BETA-RECEPTOR; CORONARY-ARTERY; MESSENGER-RNA; ALPHA-PDGF; RAT; AUTOPHOSPHORYLATION; ANGIOPLASTY; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Giese, NA COR Therapeut Inc, 256 E Grand Ave, S San Francisco, CA 94080 USA COR Therapeut Inc 256 E Grand Ave S San Francisco CA USA 94080 A
Citazione:
J.C. Yu et al., "Efficacy of the novel selective platelet-derived growth factor receptor antagonist CT52923 on cellular proliferation, migration, and suppression of neointima following vascular injury", J PHARM EXP, 298(3), 2001, pp. 1172-1178

Abstract

Exaggerated or inappropriate signaling by the platelet-derived growth factor receptor (PDGFR) tyrosine kinase has been implicated in a wide variety of diseases. Thus, a series of piperazinyl quinazoline compounds were identified as potent antagonists of the PDGFR by screening chemical libraries. Anoptimized analog, CT52923, was shown to be an ATP-competitive inhibitor that exhibited remarkable specificity when tested against other kinases, including all members of the closely related PDGFR family. The PDGFRs and stem cell 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, respectively. Other receptor tyrosine kinases, cytoplasmic tyrosine kinases, serine/threonine kinases, or members of the mitogen-activated protein kinase pathway were not significantly inhibited at 100- to 1000-fold higher concentrations. In addition, this compound also demonstrated specificity for inhibition of cellular responses. Platelet-derived growth factor-induced smooth muscle cell migration or fibroblast proliferation was found to be blocked by CT52923 with an IC50 of 64 and 280 nM, respectively, whereas 50- to 100-foldhigher concentrations were required to inhibit these responses when induced with fibroblast growth factor. To investigate the effect of CT52923 on PDGFR signaling, in vivo studies demonstrated that CT52923 could significantly inhibit neointima formation following carotid artery injury by oral administration in the rat. Therefore, PDGFR antagonism by CT52923 could be a viable strategy for the prevention of clinical restenosis or the treatment of other human diseases involving PDGFR signaling.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 12/07/20 alle ore 08:22:14