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3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2006 Dec 01; Vol. 16 (23), pp. 6049-53. Date of Electronic Publication: 2006 Sep 15. - Publication Year :
- 2006
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 0960-894X
- Volume :
- 16
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 16978863
- Full Text :
- https://doi.org/10.1016/j.bmcl.2006.08.118