Target Validation Information
Target ID T62449
Target Name Serine/threonine-protein kinase Chk1
Target Type
Clinical Trial
Drug Potency against Target 9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Drug Info IC50 = 470 nM [1]
UCN-01 Drug Info IC50 = 11 nM [2]
AZD7762 Drug Info IC50 = 5 nM [2]
3-(1H-Indol-2-yl)-1H-quinolin-2-one Drug Info IC50 = 1000 nM [3]
GRANULATIMIDE Drug Info IC50 = 80 nM [4]
A-432411 Drug Info IC50 = 7 nM [5]
9-chlorobenzo[h]isoquinolin-1(2H)-one Drug Info IC50 = 580 nM [6]
ISOGRANULATIMIDE Drug Info IC50 = 440 nM [4]
BIS-IMIDE A Drug Info IC50 = 20 nM [4]
6-(3-aminopropyl)benzo[h]isoquinolin-1(2H)-one Drug Info IC50 = 98 nM [6]
NU-6102 Drug Info IC50 < 500 nM [7]
XL844 Drug Info Ki = 2.2 nM [8]
UCN-01 Drug Info IC50 = 11 nM [9]
DEBROMOHYMENIALDISINE Drug Info IC50 = 725 nM [10]
PF-477736 Drug Info Ki = 0.49 nM [2]
Action against Disease Model UCN-01 Abrogated DNA damage-induced G2 arrest, leading to mitotic entry and subsequent cell death. [11] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Studies in Chk1 recombinant gene knockout showed that Chk1-null cells failed to maintain the DNA damage checkpoint. At the same time, these studies showed that knocking out the Chk1 gene in mice was embryonically lethal, and a conditional knockout of Chk1 induced apoptosis in embryonic stem cells in one cycle. These studies confirm that Chk1 is essential to cell cycle progression and that elimination of Chk1 will be fatal in embryonic development. [1]
References
REF 1J Med Chem. 2006 Aug 10;49(16):4896-911.4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution.
REF 2End of the line for cannabinoid receptor 1 as an anti-obesity target? An opinion. Nat Rev Drug Discov. 2009 Jul;8(7):594. doi: 10.1038/nrd2775-c1.
REF 3Bioorg Med Chem Lett. 2006 Nov 15;16(22):5907-12. Epub 2006 Sep 20.Development of 6-substituted indolylquinolinones as potent Chek1 kinase inhibitors.
REF 4Eur J Med Chem. 2008 Feb;43(2):282-92. Epub 2007 Apr 7.Synthesis, in vitro antiproliferative activities, and Chk1 inhibitory properties of pyrrolo[3,4-a]carbazole-1,3-diones, pyrrolo[3,4-c]carbazole-1,3-diones, and 2-aminopyridazino[3,4-a]pyrrolo[3,4-c]carbazole-1,3,4,7-tetraone.
REF 5Bioorg Med Chem Lett. 2010 Sep 1;20(17):5065-8. Epub 2010 Jul 13.Synthesis of selenophene derivatives as novel CHK1 inhibitors.
REF 6Bioorg Med Chem Lett. 2007 Nov 15;17(22):6280-5. Epub 2007 Sep 7.Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.
REF 7Bioorg Med Chem Lett. 2006 Mar 1;16(5):1353-7. Epub 2005 Dec 1.Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR.
REF 8The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett. 2008 Feb 1;18(3):923-8. Epub 2008 Jan 15.
REF 9The radiosensitizing agent 7-hydroxystaurosporine (UCN-01) inhibits the DNA damage checkpoint kinase hChk1. Cancer Res. 2000 Apr 15;60(8):2108-12.
REF 10Bioorg Med Chem Lett. 2004 Aug 16;14(16):4319-21.Potent inhibition of checkpoint kinase activity by a hymenialdisine-derived indoloazepine.
REF 11Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009 Jul;8(7):547-66.

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