CANCER INHIBITION BY CDK

by Selleckchem | Aug 09 2012

CYCLIN DEPENDENT KINASES OR CDK:
Cyclin dependent kinases or CDKs are also found to be very famous ones among the long list of regulators of cell cycle. These kinase enzymes play a very crucial role in various processes like mRNA processing, cellular differentiation and, transcription. These kinase enzymes have a very important kinase domain and a small structure and they also depend upon another protein i.e cyclin for their proper activity. To stop the proliferation of cancer or tumor cells these kinases can be targeted as they are an important part of cell cycle. By the inhibition of these kinase enzymes apoptosis is induced in the cells especially the tumor cells. Different kinase inhibitors have been designed to fight against these kinases and stop the inflammation, conserved in the kinase inhibitor library [1] and amongst these inhibitors, CDK inhibitors were found to be very effective ones. The inhibition of the regulators of cell cycle may also cause some hazards; so the inhibitors should be designed very carefully and efficiently in order to avoid the side effects [2].

PROPERTIES CDKs AND THEIR MODE OF ACTION:
There are different commercially available antagonists that can be used against the CDK pathway. The process of regulation of cell cycle may restarts by using these inhibitors. Many types of CDKs are present inside the cell that play their role during specific steps of cell cycle and are associated with different functions of the cell, hence their similarity and difference in structure must be considered when designing the inhibitor molecules against these CDKs. Among these inhibitors, some are pan CDK inhibitors and some are Cycline A-H inhibitor. For example some CDK inhibitors include Flavopiridol, Selicilib and Roscovitine. The examples of some CDKs include the derivatives of pyrimidines, oxo-or thio-flavopiridols and aminothiazoles, they are also seen to inhibit the CDKs vey selectively and effectively. For instance, to inhibit specifically the CDK4, the suggested inhibitor is PD 0332991 [3]. These inhibitors are commercially available and can easily be bought for any purpose from the relevant suppliers.

CDK INHIBITORS: CLINICAL TRIALS
One important CDK inhibitor named Flavopiridol was discovered two decades ago. It is a very well known CDKS inhibitor that was the first CDK inhibitor to b brought in the clinics for the study [4]. An example of pan inhibitors is Alvocidib that has been used to treat the arthritis and CLL or Chronic lymphocytic leukemia patients [5]. Some properties also including pharmacokinetics of this inhibitor was critically analyzed during the phase I clinical trials on the patients suffering from acute leukemia [6]. So far as the mode of activity of Flavopiridol is concerned, it has been studied, observed and reported to increase the Bcl-2 expression and decrease the expression levels of some oncogenic transcription factors [7]. Flavopiridol has been observed to be effectively as single and in combination with other drugs for the therapy. Patent has been done when Flavopiridol was used in combination with Glivec and this combination is was found to be very effective against the cells of BCR/ABL leukemia. Clinical trials of phase I related to this drug have revealed its effectiveness in refractory CLL and it was reported to control the disease very efficiently [8]. Flavopiridol has exhibited synergistic effects when applied along with Etoposide, Paclitaxel, Topotecane and Doxorubicin etc [9]. Clinical trials on this inhibitor are still going on to gain better results so efficient monitoring of schedule, timing and pattern of administration is required.

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.
S1225	Etoposide	Etoposide is a semisynthetic derivative of podophyllotoxin, which inhibits DNA synthesis via topoisomerase II inhibition activity which enhances double-strand and single-strand cleavage of DNA and reversibly inhibits repair by topoisomerase II binding. Etoposide induces autophagy, mitophagy and apoptosis.
S1150	Paclitaxel	Paclitaxel is a microtubule polymer stabilizer with IC50 of 0.1 pM in human endothelial cells.Paclitaxel can cause both mitotic arrest and apoptotic cell death. Paclitaxel also induces autophagy.
S1231	Topotecan HCl	Topotecan HCl is a topoisomerase I inhibitor for MCF-7 Luc cells and DU-145 Luc cells with IC50 of 13 nM and 2 nM in cell-free assays, respectively. Topotecan HCl induces autophagy and apoptosis.
S1208	Doxorubicin (DOX) HCl	Doxorubicin (DOX) HCl is an antibiotic agent that inhibits human DNA topoisomerase I and topoisomerase II with IC50s of 0.8 μM and 2.67 μM, respectively. Doxorubicin reduces basal phosphorylation of AMPK. Doxorubicin is used in the concomitant treatment of HIV-infected patients but is found to be at high risk of HBV reactivation.This product may precipitate when dissolved in PBS solution. It is recommended to prepare the stock solution in pure water and dilute with either pure water or saline to obtain the working solution.