Cyclin-dependent kinase 2, inhibition

Rohitukine (112) Flavone Alvocidib (flavopiridol, HMR 1275) (113) Oncology Cyclin-dependent kinase inhibition Phase III (NSCLC) Phase Ilb (CLL) Sanofi-Aventis 700-702... 

Endicott, J.A., Noble, M.E. and Tucker, J.A. (1999) Cyclin-dependent kinases inhibition and substrate recognition. Curr.Opin.Stmct.Biol., 9, 738-744. 

Skalnikova, H., Halada, P., Dzubak, P., Hajduch, M., Kovarova, H. (2005). Protein fingerprints of anti-cancer effects of cyclin-dependent kinase inhibition Identification of candidate biomarkers using 2-D liquid phase separation coupled to mass spectrometry. Technology in Cancer Research Cf Treatment, 4, 447—454. 

Cyclin-dependent kinase inhibition by flavoalkaloids 12MRM632. Design and synthesis of bicycUc azasugars, carbasugars and related molecules as glycosidase inhibitors 13CSR5102. 

The pyrrole ring is widely distributed in nature. It occurs in both terrestrial and marine plants and animals [1-3]. Examples of simple pyrroles include the Pseudomonas metabolite pyrrolnitrin, a recently discovered seabird hexahalogenated bipyrrole [4], and an ant trail pheromone. An illustration of the abundant complex natural pyrroles is konbu acidin A, a sponge metabolite that inhibits cyclin-dependent kinase 4. The enormous reactivity of pyrrole in electrophilic substitution reactions explains the occurrence of more than 100 naturally occurring halogenated pyrroles [2, 3]. 

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. 

Kanungo J, Zheng YL, Amin ND, Kaur S, Ramchandran R, Pant HC (2009) Specific inhibition of cyclin-dependent kinase 5 activity induces motor neuron development in vivo. Biochem Biophys Res Commun 386 263-267... 

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... 

Zi, X.L. et al., A flavonoid antioxidant, silymarin, inhibits activation of erbBl signaling and induces cyclin-dependent kinase inhibitors, G1 arrest and anticarcinogenic effects in human prostate carcinoma DU145 cells, Cancer Res., 58, 1920, 1998. 

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. 

Another bromopyrrol from Hymeniacidon, konbuacidin A (196), inhibits cyclin dependent kinase 4 (cdk4) with an IC5o value of 20 pg/ml but is not cytotoxic to L1210 and KB cells [156]. 

Spongiacidins A (197) and B (198), azepine-type bromopyrrole alkaloids from Hymeniacidon which are geometrical isomers of hymenialdisine (171), inhibit c-erbB-2 kinase (IC50 9.0 and 8.5 pg/ml) and cyclin dependent kinase 4 (IC50 32 and 12 pg/ml) [157],... 

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)...

Meijer L, Thunnissen A-MWH, White AW, Gamier M, Nikolic M, Tsai L-H, Walter J, Cleverley KE, Salinas PC, Wu Y-Z, Biemat J, Mandelkow E-M, Kim S-H, Pettit GR (2000) Inhibition of Cyclin-Dependent Kinases, GSK-3P and CK1 by Hymenialdisine, a Marine Sponge Constituent. Chem Biol 7 51... 

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