1. 3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.
- Author
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Fraley ME, Steen JT, Brnardic EJ, Arrington KL, Spencer KL, Hanney BA, Kim Y, Hartman GD, Stirdivant SM, Drakas BA, Rickert K, Walsh ES, Hamilton K, Buser CA, Hardwick J, Tao W, Beck SC, Mao X, Lobell RB, Sepp-Lorenzino L, Yan Y, Ikuta M, Munshi SK, Kuo LC, and Kreatsoulas C
- Subjects
- Cell Cycle drug effects, Cell Line, Tumor, Checkpoint Kinase 1, Crystallography, X-Ray, Humans, Indazoles metabolism, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors metabolism, Structure-Activity Relationship, Indazoles chemistry, Indazoles pharmacology, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinases chemistry, Protein Kinases metabolism
- 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.
- Published
- 2006
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