title: Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.
abstract: A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.
authors.affiliation: Novartis Institute for BioMedical Research, CH-4002 Basel, Switzerland. vito.guagnano@novartis.com
authors.forename: Vito
authors.initials: V
authors.lastname: Guagnano
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Carsten
authors.initials: C
authors.lastname: Spanka
authors.forename: Vincent
authors.initials: V
authors.lastname: Bordas
authors.forename: Mickaël
authors.initials: M
authors.lastname: Le Douget
authors.forename: Christelle
authors.initials: C
authors.lastname: Stamm
authors.forename: Josef
authors.initials: J
authors.lastname: Brueggen
authors.forename: Michael R
authors.initials: MR
authors.lastname: Jensen
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.forename: Herbert
authors.initials: H
authors.lastname: Schmid
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.forename: Joerg
authors.initials: J
authors.lastname: Berghausen
authors.forename: Peter
authors.initials: P
authors.lastname: Drueckes
authors.forename: Alfred
authors.initials: A
authors.lastname: Zimmerlin
authors.forename: Dirksen
authors.initials: D
authors.lastname: Bussiere
authors.forename: Jeremy
authors.initials: J
authors.lastname: Murray
authors.forename: Diana
authors.initials: D
authors.lastname: Graus Porta
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D001749:Urinary Bladder Neoplasms
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; C568950:infigratinib; D020794:Receptor Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3