Protein inhibit cyclin-dependent kinase

Olomucine (46), originally isolated from the cotyledons of radish (Raphanus sativus L.A.) provided the natural product model for the synthetic agent roscovitine (47). Olomucine (46) inhibits cyclin-dependent kinases, proteins that play a major role in cell cycle progression. R-Roscovitine is currently in Phase II clinical trials... 

Leclerc, S., Garnier, M., Hoessel, R. (2001) et al. Indirubins inhibit glycogen synthase kinase-3 3 and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer s disease. A property common to most cyclin-dependent kinase inhibitors. J. Biol. Chem., 276, 251-260. 

Negative control of CDK activity in the cell cycle is performed by specific inhibitor proteins known as cyclin-dependent kinase inhibitors, CKIs (review Morgan, 1995 Pines, 1995 Peter, 1997). These are a heterogenous family of proteins that may associate with a CDK or with a CDK-cyclin complex in a reversible maimer, inhibiting CDK activity. 

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)...

Resveratrol exerts antitumor effects partly by arresting the growth of various cancer cells in culture [Kundu and Surh, 2004]. The inhibition of ornithine decarboxylase (ODC), a biochemical hallmark of tumor promotion, has been shown to account for the antiproliferative and antitumor effects of resveratrol [Schneider et al., 2000 Ulrich et al., 2007]. Aberrant changes in cell-cycle machinery are considered as the biochemical basis of abnormal proliferation of transformed cells. Major cell-cycle regulatory proteins include various cyclins, cyclin-dependent kinases (Cdk), Cdk inhibitors, and check point kinases (Chkl... 

Sirolimus binds to an intracellular receptor protein and elevates p27 levels, which leads to inhibition of cyclin-dependent kinase (CDK) complexes, and ultimately induces cell-cycle arrest in the late GI phase. It inhibits proliferation of both rat and human SMCs in vitro and reduces intimal thickening in models of vascular injury (29,30). Sirolimus inhibits... 

Recently considerable attention has been focused on the metabolites belonging to bisindolylmaleimides such as staurosporine (28) [12], UCN-01 (29) [13], rebeccamycin (30) [14], which were produced by the family of Streptomyces, Actinomycetes, and Saccharothrixes. These metabolites cause topoisomerase I mediated DNA cleavage, potent inhibition of protein kinase C and cell-cycle-regulating cyclin-dependent kinase (CDK), and cell-cycle checkpoint inhibition [15]. It seems interesting that myxomycetes also contain the bisindole metabolites having related structures to 28 - 30. 

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