title: 3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. alee7@prdus.jnj.com <alee7@prdus.jnj.com>
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: Justin T
authors.initials: JT
authors.lastname: Steen
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brnardic
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Keith L
authors.initials: KL
authors.lastname: Spencer
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hanney
authors.forename: Yuntae
authors.initials: Y
authors.lastname: Kim
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.forename: Bob A
authors.initials: BA
authors.lastname: Drakas
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Eileen S
authors.initials: ES
authors.lastname: Walsh
authors.forename: Kelly
authors.initials: K
authors.lastname: Hamilton
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: James
authors.initials: J
authors.lastname: Hardwick
authors.forename: Weikang
authors.initials: W
authors.lastname: Tao
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Beck
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Mao
authors.forename: Robert B
authors.initials: RB
authors.lastname: Lobell
authors.forename: Laura
authors.initials: L
authors.lastname: Sepp-Lorenzino
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.forename: Mari
authors.initials: M
authors.lastname: Ikuta
authors.forename: Sanjeev K
authors.initials: SK
authors.lastname: Munshi
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Constantine
authors.initials: C
authors.lastname: Kreatsoulas
mesh_terms: 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
chemical_list: D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1