Cyclin-dependent Kinases CDKs

Cell Cycle Control. Figure 1 Cell cycle regulation by Cyclin dependent kinases (CDKs). Different cyclins bound to different CDKs promote the transition from one cell cycle phase into another. CDK-dependent phosphorylation of Rb is required to release active E2F transcription factors, which promotes entry into S phase. 

Aryl-substituted pyrrolizinones 90 were examined for their potential as inhibitors of the cytochrome P450 aromatase <2000BMC945>. Some benzo-annulated tetrahydropyrrolizinones were evaluated as inhibitors of cyclin-dependent kinases (CDKS) <2001JME4615>. 

In 1998-99, she worked on the synthesis of cyclin-dependent kinase (CDK) inhibitors, under the direction of Professor Miguel F. Brana at University San Pablo (CEU, Spain). 

Cell cycle is one of the physiological processes in which the role of uhiquitin—proteasome-mediated proteolysis is well established. With the advent of yeast mutants that interfered with various phases of the cell cycle, cyclin-dependent kinases (Cdks) were found to have a critical role in regulating the cell cycle. Typically, Cdks activated hy regulatory proteins are known as cyclins. Different Cdk—cyclin complexes are formed at specific stages of the cell cycle such as the S-phase (in which DNA synthesis occurs) and the metaphase. The transition from metaphase to anaphase depends on degradation of cyclins. " " Systematic biochemical studies showed that cyclins were substrates for the uhiquitin—proteasome pathway (Table 5). 

Non-receptor serine/threonine kinases and dual specificity kinases cAMP-dependent protein kinase (PKA) Phosphoinositol-3-kinase (PI-3K) Cyclin-dependent kinase (CDK) Mitogen-activated protein kinase (MAPK) MAPKK (ERK)... 

Starfish and human cycline-dependent kinases (CDKs) Indimbin-3 -monoxime inhibits CDKs with IC50 =0.18 irM 133... 

An oxime derivative of indirubin (a natural bis-indole alkaloid used in traditional Chinese medicine to treat chronic myelocytic leukemia), indirubin-3 -monoxime (37), was found to be a potent inhibitor of cyclin-dependent kinases (CDKs), and of the proliferation of myeloid leukemia cells via inhibition of a tyrosine kinase . The 3D structure of the complex of 37 with CDK revealed that the oxime function is intact, and that it occupies the ATP-ribose site of the CDK-ATP structure. While the specific role of the oxime group in the biological activity of 37 is not clear, it was proposed that its reactivity may be utilized for further drug design... 

Ro-4584820, a cyclin-dependent kinase (CDK) inhibitor, is in Phase 1 of clinical evaluation. CDKs are a family of serine/threonine protein kinases that play key roles in the normal growth and life cycle of eukaryotic cells. 

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... 

Keppler et al. have synthesised Ru11 and Os11 arene complexes with paullones as ligands to confer solubility on these otherwise insoluble cyclin-dependent kinase (CDK) inhibitors [152]. No dramatic differences between the ruthenium and the osmium complexes were found in the IC50 values against A549, CHI and SW480 cancer cell lines. 

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. 

Figure 24.23. Cyclin expression is regulated according to the cell cycle. (A) The regulatory subunits of the cyclin-dependent kinases (CDKs) are referred to as cyclins because these proteins are synthesized and degraded during the cell cycle. (Adapted from Weinberg RA Biology of Cancer 2007.) (B) Specific cyclins bind to and activate specific CDKs, and this propels the cell through specific stages of the cell cycle.

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