CDK INHIBITOR AND CELL CYCLE

by Selleckchem | Jul 27 2012

CYCLIN DEPENDENT KINASES OR CDKs:
Cyclin dependent kinases are amongst one of the most vital kinase enzymes in the regulation of cell cycle. These are also abbreviated as CDKs and due to a crucial role these enzymes are implicated in transcription, nerve cells differentiation, and mRNA processing. These enzymes have small structure but having an important part that is kinase domain. It is reported that the inhibition of CDK leads to the apoptosis of cells specifically in case of cancer cells, so it is important in controlling the cell cycle. Uncontrolled cellular proliferation can lead to the cell cycle aberrations. Various compounds found in kinase inhibitor library have shown activity against inflammations and cancer [1] and among these inhibitors CDK inhibitors are most effective against CDKs. The development of inhibitors has to be performed carefully as there may be some of the other potential hazards of cell cycle dysregulation and some other effects as well [2].

MECHANISM OF ACTION OF CDK INHIBITOR AND PROPERTIES:
CDK pathway can be checked by using various antagonists of CDK which are commercially available and these are used to restart the cell cycle regulation. There are many types of CDKs which play vital roles in the cellular functions, so more than one inhibitor of CDK kinases are required to develop. Some of these are CDK2 inhibitor and others are pan CDK inhibitor. Some of the famous CDK inhibitors are Roscovitine, Flavopiridol and Seliciclib. Some of the derived compounds from aminothiazoles, thio-or oxo-flavopiridols and pyrimidines are also noted to be powerful selective CDK inhibitors. For CDK4 specific inhibition PD 0332991 is a specific inhibitor [3]. These inhibitors are available from any of the supplier if someone wants to buy it.

CDK INHIBITORS IN CLINICS:
More than twenty years ago Flavopiridol was discovered, a famous CDK antagonist which later on was observed as CDK inhibitor. This was the first CDK inhibitor in clinical trials [4]. Arthritis and CLL or chronic lymphocytic leukemia has been treated with Alvocidib which is a pan CDK inhibitor [5]. During clinical trials phase I properties like pharmacokinetics of Flavopiridol were assessed on acute leukemia patients [6]. The mechanism of action of this inhibitor was noted as it affects on Bcl-2 expression enhancement and on the other hand decreasing the oncogenic transcription factors expression [7]. A patent has also been done for its use with Glivec for the treatment of leukemia cells having BCR/ABL kinase positive. In another study during phase I of clinical trials the administration of this inhibitor was designed to control the refractory CLL efficiently [8]. This drug has been used significantly as a single agent but this is also used in combination with other drugs like Doxorubicin, Etoposide, Topotecane and Paclitaxel etc. for a synergistic effect [9]. But in order to get best results, pattern, schedule and administration timing of this drug has to be monitor properly.

REFERENCES:
1. Rossi A, e.a., Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Medicine, 2006.
2. Sausville, E., Complexities in the development of cyclin-dependent kinase inhibitor drugs. Trends in Molecular Medicine, 2002.
3. Fry DW, e.a., Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther., 2004.
4. Senderowicz, A., Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs, 2006.
5. Sekine C, e.a., Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors. J. Immunol., 2008.
6. Karp JE, e.a., Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias Blood, 2010.
7. Nelson DM, e.a., Flavopiridol induces BCL-2 expression and represses oncogenic transcription factors in leukemic blasts from adults with refractory acute myeloid leukemia. Leukemia and Lymphoma, 2011.
8. Byrd JC, e.a., Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia Blood, 2006.
9. Bible KC, a.K.S., Cytotoxic Synergy between Flavopiridol (NSC 649890, L86-8275) and Various Antineoplastic Agents: The Importance of Sequence of Administration. Cancer Res, 1997.

Cat.No.	Product Name	Information
S1116	Palbociclib (PD-0332991) HCl	Palbociclib (PD-0332991) HCl is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM in cell-free assays, respectively. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. Phase 3.
S1230	Flavopiridol (Alvocidib)	Flavopiridol (Alvocidib) competes with ATP to inhibit CDKs including CDK1, CDK2, CDK4, CDK6, and CDK9 with IC50 values in the 20-100 nM range. It is more selective for CDK1, 2, 4, 6, 9 versus CDK7. Flavopiridol is initially found to inhibit EGFR and PKA. Flavopiridol induces autophagy and ER stress. Flavopiridol blocks HIV-1 replication. Phase 1/2.
S1153	Roscovitine	Roscovitine is a potent and selective CDK inhibitor for Cdc2, CDK2 and CDK5 with IC50 of 0.65 μM, 0.7 μM and 0.16 μM in cell-free assays. It shows little effect on CDK4/6. Phase 2.