Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors.
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.
Kim
Kyoung Soon
KS
Department of Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. kyoung.kim@bms.com
Lu
Songfeng
S
Cornelius
Lyndon A
LA
Lombardo
Louis J
LJ
Borzilleri
Robert M
RM
Schroeder
Gretchen M
GM
Sheng
Christopher
C
Rovnyak
George
G
Crews
Donald
D
Schmidt
Robert J
RJ
Williams
David K
DK
Bhide
Rajeev S
RS
Traeger
Sarah C
SC
McDonnell
Patricia A
PA
Mueller
Luciano
L
Sheriff
Steven
S
Newitt
John A
JA
Pudzianowski
Andrew T
AT
Yang
Zheng
Z
Wild
Robert
R
Lee
Frances Y
FY
Batorsky
Roberta
R
Ryder
James S
JS
Ortega-Nanos
Marie
M
Shen
Henry
H
Gottardis
Marco
M
Roussell
Deborah L
DL
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
C470243:KIF11 protein, human; D011758:Pyrroles; D016547:Kinesins