Title of article
3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6
Author/Authors
Mark E. Fraley، نويسنده , , Justin T. Steen، نويسنده , , Edward J. Brnardic، نويسنده , , Kenneth L. Arrington، نويسنده , , Keith L. Spencer، نويسنده , , Barbara A. Hanney، نويسنده , , Yuntae Kim، نويسنده , , George D. Hartman، نويسنده , , Steven M. Stirdivant، نويسنده , , Bob A. Drakas، نويسنده , , Keith Rickert، نويسنده , , Eileen S. Walsh، نويسنده , , Kelly Hamilton، نويسنده , , Carolyn A. Buser، نويسنده , , James Hardwick، نويسنده , , Weikang Tao، نويسنده , , Stephen C. Beck، نويسنده , , Xianzhi Mao، نويسنده , , Robert B. Lobell، نويسنده , , Laura Sepp-Lorenzino، نويسنده , , et al.، نويسنده ,
Issue Information
روزنامه با شماره پیاپی سال 2006
Pages
5
From page
6049
To page
6053
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 IC50 = 0.30 nM) 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.
Keywords
Chek1 kinase , DNA damage , CDK7 kinase , Oncology , indazoles , indoles , Checkpoint escape
Journal title
Bioorganic & Medicinal Chemistry Letters
Serial Year
2006
Journal title
Bioorganic & Medicinal Chemistry Letters
Record number
797525
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