title: Discovery of the pyrrolo[2,1-f][1,2,4]triazine nucleus as a new kinase inhibitor template.
abstract: The pyrrolo[2,1-f][1,2,4]triazine nucleus was identified as a novel kinase inhibitor template which effectively mimics the well-known quinazoline kinase inhibitor scaffold. Attachment of a 4-((3-chloro-4-fluorophenyl)amino) substituent to the template provided potent biochemical inhibitors of the tyrosine kinase activity of EGFR, as well as inhibition of cellular proliferation of the human colon tumor cell line DiFi. Attachment of a 4-((3-hydroxy-4-methylphenyl)amino) substituent provided potent inhibitors of VEGFR-2 which also showed effects on the VEGF-dependent proliferation of human umbilical vein endothelial cells. Biological activity was maintained with substitution at positions 5 or 6, but not 7, suggesting that the former positions are promising sites for introducing side chains which modulate physicochemical properties. Preliminary inhibition studies with varying ATP concentrations suggest that, like the quinazoline-based kinase inhibitors, the pyrrolotriazine-based inhibitors bind in the ATP pocket.
authors.affiliation: Departments of Oncology Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, New Jersey 08543-4000, USA. john.hunt@bms.com
authors.forename: John T
authors.initials: JT
authors.lastname: Hunt
authors.forename: Toomas
authors.initials: T
authors.lastname: Mitt
authors.forename: Robert
authors.initials: R
authors.lastname: Borzilleri
authors.forename: Johnni
authors.initials: J
authors.lastname: Gullo-Brown
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Brian
authors.initials: B
authors.lastname: Fink
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Han
authors.forename: Steven
authors.initials: S
authors.lastname: Mortillo
authors.forename: Gregory
authors.initials: G
authors.lastname: Vite
authors.forename: Barri
authors.initials: B
authors.lastname: Wautlet
authors.forename: Tai
authors.initials: T
authors.lastname: Wong
authors.forename: Chiang
authors.initials: C
authors.lastname: Yu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zheng
authors.forename: Rajeev
authors.initials: R
authors.lastname: Bhide
mesh_terms: D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D018716:Molecular Mimicry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011799:Quinazolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D011758:Pyrroles; D011799:Quinazolines; D014227:Triazines; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2