title: New C-5 substituted pyrrolotriazine dual inhibitors of EGFR and HER2 protein tyrosine kinases.
abstract: Novel C-5 substituted pyrrolotriazines were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. The lead compound exhibited promising oral efficacy in both EGFR and HER2 driven human tumor xenograft models. It is hypothesized that its C-5 morpholine side chain binds in the ribose phosphate portion of the ATP binding pocket.
authors.affiliation: Department of Oncology Chemistry, 5 Research Parkway, Wallingford, CT 06492-1951, USA. harold.mastalerz@bms.com
authors.forename: Harold
authors.initials: H
authors.lastname: Mastalerz
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Pierre
authors.initials: P
authors.lastname: Dextraze
authors.forename: Brian E
authors.initials: BE
authors.lastname: Fink
authors.forename: Ashvinikumar
authors.initials: A
authors.lastname: Gavai
authors.forename: Bindu
authors.initials: B
authors.lastname: Goyal
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Han
authors.forename: Walter
authors.initials: W
authors.lastname: Johnson
authors.forename: David
authors.initials: D
authors.lastname: Langley
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Arvind
authors.initials: A
authors.lastname: Mathur
authors.forename: Simone
authors.initials: S
authors.lastname: Oppenheimer
authors.forename: Edward
authors.initials: E
authors.lastname: Ruediger
authors.forename: James
authors.initials: J
authors.lastname: Tarrant
authors.forename: John S
authors.initials: JS
authors.lastname: Tokarski
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
authors.forename: Dolatrai M
authors.initials: DM
authors.lastname: Vyas
authors.forename: Henry
authors.initials: H
authors.lastname: Wong
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
authors.forename: Guifen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009368:Neoplasm Transplantation; D010710:Phosphates / Q000737:chemistry; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012266:Ribose / Q000737:chemistry; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000255:Adenosine Triphosphate; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D010710:Phosphates; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D012266:Ribose; D014227:Triazines