title: Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors.
abstract: Synthesis and SAR of substituted pyrrolotriazine-4-one analogues as Eg5 inhibitors are described. Many of these analogues displayed potent inhibitory activities in the Eg5 ATPase and A2780 cell proliferation assays. In addition, pyrrolotriazine-4-one analogue 26 demonstrated in vivo efficacy in an iv P388 murine leukemia model. Both NMR and X-ray crystallographic studies revealed that these analogues bind to an allosteric site on the Eg5 protein.
authors.affiliation: Department of Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. kyoung.kim@bms.com
authors.forename: Kyoung Soon
authors.initials: KS
authors.lastname: Kim
authors.forename: Songfeng
authors.initials: S
authors.lastname: Lu
authors.forename: Lyndon A
authors.initials: LA
authors.lastname: Cornelius
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Lombardo
authors.forename: Robert M
authors.initials: RM
authors.lastname: Borzilleri
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Schroeder
authors.forename: Christopher
authors.initials: C
authors.lastname: Sheng
authors.forename: George
authors.initials: G
authors.lastname: Rovnyak
authors.forename: Donald
authors.initials: D
authors.lastname: Crews
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmidt
authors.forename: David K
authors.initials: DK
authors.lastname: Williams
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Bhide
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Traeger
authors.forename: Patricia A
authors.initials: PA
authors.lastname: McDonnell
authors.forename: Luciano
authors.initials: L
authors.lastname: Mueller
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Pudzianowski
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.forename: Frances Y
authors.initials: FY
authors.lastname: Lee
authors.forename: Roberta
authors.initials: R
authors.lastname: Batorsky
authors.forename: James S
authors.initials: JS
authors.lastname: Ryder
authors.forename: Marie
authors.initials: M
authors.lastname: Ortega-Nanos
authors.forename: Henry
authors.initials: H
authors.lastname: Shen
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Roussell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C470243:KIF11 protein, human; D011758:Pyrroles; D016547:Kinesins