Cyclin-dependent kinase-5 CDK

Raynaud and co-workers recently reported the optimization of inhibitors of cyclin-dependent kinase-2 (CDK-2), based on a purine scaffold (Scheme 7). The synthesis... 

Another simple approach for the detection of noncovalent interactions is to compare the peptide maps produced by proteolysis of the target protein and its complex with other ligands. This approach, also known as epitope mapping, relies on the fact that the two maps differ qualitatively because the contact regions of the interacting proteins are shielded from the protease s activity in the complex. An illustrative example is the detection of protein-protein interaction between a protein representing the kinase inhibitory domain of the cell cycle regulatory protein (p21-B) and cyclin-dependent kinase 2 (cdk).164... 

Pan, M.H., Chen, W.J., Lin-Shiau, S.Y., Ho, C.T., and Lin, J.K., Tangeretin induces cell cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis, 23 (10), 101, 2002. 

Liang, Y. C., Lin-Shiau, S. Y, Chen, C. R, and Lin, J. K. 1999. Inhibition of cyclin-dependent kinases 2 and 4 activities as well as induction of Cdk inhibitors p21 and p27 during growth arrest of human breast carcinoma cells by (-)-epigallocatechin-3-gal-late. J. Cell. Biochem. 75 1-12. 

Fig. 4.3 Mechanism of action of sirolimus. Sirolimus readily diffuses into the cytoplasm of the target cells where it binds to immunophilins (FK506-BP). The sirolimus-immunophilin complex does not inhibit calcineurin activity instead it binds to the mTOR. The sirolimus-immunophilin-mTOR complex stops the cell cycle progression from G1 to S phase. The targets of sirolimus include the eukaryotic initiation factor (eIF-4F), 70-kDa S6 protein kinase (p70S6 K) and several cyclin-dependent kinases (cdk). As a consequence, it blocks downstream signaling pathway initiated after activation of IL-2 receptors, resulting in blockage of T-cell proliferation (see Color Insert)...

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>. 

Most phytopolyphenols, such as tea polyphenols, genistein, and silymarin, can produce cell arrest at G1 phase through inhibiting cyclin dependent kinase (cdk-2 and cdk-4) activities and inducing Cdk inhibitors p21 and p27. 

Figure 1 Overview of the different phases of the cell cycle. Quiescent cells are in GO phase and reenter the cell cycle at Gl during which cells prepare for DNA synthesis. After passing the restriction point in late Gl cells are committed to enter S phase, during which DNA replication occurs. Cells in G2 phase prepare for mitosis (M phase). Cell cycle progression is controlled by various positive and negative cell cycle regulatory proteins including cyclins (A, B, D, E) cyclin dependent kinases (cdk 1,2, 4, 6) cdk inhibitors (p15, p16, p18, p19, p21, p27, p57), retinoblastoma (Rb) and p53.

Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. 1996. Flavopiri-dol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 56 2973-78... 

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