3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.
The development of 3-(indol-2-yl)indazoles as inhibitors of Chek1 kinase is described. Introduction of amides and heteroaryl groups at the C6 position of the indazole ring system provided sufficient Chek1 potency and selectivity over Cdk7 to permit escape from DNA damage-induced arrest in a cellular assay. Enzyme potency against Chek1 was optimized by the incorporation of a hydroxymethyl triazole moiety in compound 21 (Chek1 IC(50)=0.30nM) that was shown by X-ray crystallography to displace one of three highly conserved water molecules in the HI region of the ATP-binding cleft.
Fraley
Mark E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. alee7@prdus.jnj.com <alee7@prdus.jnj.com>
Steen
Justin T
JT
Brnardic
Edward J
EJ
Arrington
Kenneth L
KL
Spencer
Keith L
KL
Hanney
Barbara A
BA
Kim
Yuntae
Y
Hartman
George D
GD
Stirdivant
Steven M
SM
Drakas
Bob A
BA
Rickert
Keith
K
Walsh
Eileen S
ES
Hamilton
Kelly
K
Buser
Carolyn A
CA
Hardwick
James
J
Tao
Weikang
W
Beck
Stephen C
SC
Mao
Xianzhi
X
Lobell
Robert B
RB
Sepp-Lorenzino
Laura
L
Yan
Youwei
Y
Ikuta
Mari
M
Munshi
Sanjeev K
SK
Kuo
Lawrence C
LC
Kreatsoulas
Constantine
C
D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D018360:Crystallography, X-Ray; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1