Checkpoint kinase-1 inhibitors

Case Study VS for Checkpoint Kinase-1 inhibitors using Knowiedge-Based VS... 

Collins I, Garrett MD. 2005. Targeting the cell division cycle in cancer CDK and cell cycle checkpoint kinase inhibitors. Curr Opin Pharmacol 5 366-373. 

Terrell J, Shih S, Dunn R, Hicke L (1998) A function for monoubiquitination in the internalization of a G protein-coupled receptor. Mol Cell 1 193-202 Tomoda K, Kubota Y, Kato J (1999) Degradation of the cydin-dependent-kinase inhibitor p27 is instigated by Jabl. Nature 398 160-165 Toyoshima F, Moriguchi T, Wada A, Fukuda M, Nishida, E (1998) Nudear export of cydin Bl and its possible role in the DNA damage-induced G2 checkpoint. EMBO J 17 2728-2735... 

S. Chakravarty, S. Dugar (2002). Inhibitors of p38a MAL kinase. A m<. Rep. Med. Chem. 37 111. Y. Dai, S. Grant (2003). Cyclin-dependent kinase inhibitors. Curr. Opin. Pharmacol. 3 362-370. S. D. Kimball, K. R. Webster (2001). Cell cycle kinases and checkpoint regulation in cancer. Annu. Rep. Med. Chem. 36 139. 

Isothiazoles have been incorporated into selective ChK2 (checkpoint kinase 2) inhibitor 212 <07BMCL172> and HCV (hepatitis C virus) NS5B polymerase inhibitor 213 <07BMCL28>, sultam into CDK (cyclin-dependent kinase) inhibitor 214 <07BMCL1284>, and trioxo-benzoisothiazole into the non-hepatotoxic acetaminophen analog 215 <07BMC2206>. 

Other mechanisms of action involve inhibitors of the heat shock protein Hsp-90, of checkpoint kinases, and inhibitors of protein degradation by interaction with the proteasome. 

Control of the various phases of the growth cyde is exerted by the cyclical activation and repression of the cyclin-dependent kinases. Two important regulators of the cell cycle have been now shown to participate in acute renal failure. One family of proteins, the cycUn-dependent kinase inhibitors, which bind to and inhibit assembled cyclin kinases, and in particular the cycUn-dependent kinase inhibitor protein p21 is expressed in all forms of renal failure studied, induding ischemia-reperfusion, cisplatin and obstructive uropathy. This protein binds to and inhibits the CDKs that regulate the Gl/S a G2/M transition. P21 expression is enhanced by hostile environmental conditions [82]. The function of these checkpoints is to monitor the fidelity of DNA rephcation and other macromolecular components of the cell necessary for accurate reproduction... 

Gadea, B. B., Ruderman, J. V. (2005). Aurora kinase inhibitor ZM447439 blocks chromosome-induced spindle assembly, the completion of chromosome condensation, and the establishment of the spindle integrity checkpoint in Xenopus egg extracts. Molecular Biology of the Cell, 16, 1305—1318. 

G. I. (2006). The Aurora kinase inhibitor VX-680 induces endor-eduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function. Cancer Research, 66, 7668—7677. 

The cyclin-dependent kinase inhibitors such as p21 and pl6 proteins play central roles in this process. These proteins exert their functions by combining with cyclins/CDKs complexes, conducting finally to the blockage of the cell cycle at Gl-S checkpoint [131,132]. 

UCN-01 [20] (http //www.novartisoncology.com/research-innovatiOTi/pipeline. jsp) also known as 7-hydroxystaurosporine, is a non-specific inhibitor of kinases with good activity against PKC, the cyclin-dependent kinases (CDKs) and checkpoint kinase I (Chkl), and it is in phase II studies for the potential treatment of cancer - in particular chronic lymphocytic leukemia. 

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