2hog
crystal structure of Chek1 in complex with inhibitor 20
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OverviewOverview
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.
About this StructureAbout this Structure
2HOG is a Single protein structure of sequence from Homo sapiens with 710 as ligand. Active as Non-specific serine/threonine protein kinase, with EC number 2.7.11.1 Full crystallographic information is available from OCA.
ReferenceReference
3-(Indol-2-yl)indazoles as Chek1 kinase inhibitors: Optimization of potency and selectivity via substitution at C6., 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, Kreatsoulas C, Bioorg Med Chem Lett. 2006 Dec 1;16(23):6049-53. Epub 2006 Sep 15. PMID:16978863
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