CANCER AND CDK INHIBITION

by Selleckchem | Sep 16 2012

CDK/CYCLIN DEPENDENT KINASES:
Among a large number of cell cycle regulators, cyclin dependent kinases also known as CDKs are known to be very important ones. These kinases play a crucial role in the processes of transcription, mRNA processing and cellular differentiation. These kinases have a small structure with an important kinase domain and depend on another small protein for proper activity i.e., cyclin. As these are very important kinases in cell cycle, they can be targeted in order to prevent proliferation of cancer cells. Inhibition of these kinases has shown induction of apoptosis especially in cancer cells. Various inhibitors have been designed against different kinases to fight cancer and inflammation, preserved in kinase inhibitor library for screening [1] amongst these CDK2 inhibitors have been found to be most effective. Inhibiting cell cycle regulators may have some hazards as well; therefore inhibitors should be developed carefully in order to avoid these side effects [2].

PROPERTIES AND MODE OF ACTION:
Various antagonists available commercially that are used against CDK pathway. These inhibitors may restart the process of cell cycle regulation. Different types of CDKs are there in the cell that function in specific cell cycle steps and are involved in regulation f different cellular functions, therefore, their structure similarity and difference should be considered while designing inhibitors against these CDKs. Some of these CDK inhibitors are Cycline e inhibitor and pan CDK inhibitor. Examples of some of the CDK inhibitors are Seliciclib, Flavopiridol and Roscovitine. Other than these examples, some derivatives of aminothiazoles, pyrimidines and oxo-or thio-flavopiridols have also been made and are observed to inhibit CDKs quite effectively and selectively. For example for inhibition of CDK4 specifically, PD 0332991 inhibitor has been suggested [3]. These inhibitors can be bought from the suppliers of inhibitors for any purpose.

CLINICAL TRIALS OF CDK INHIBITORS:
Flavopiridol one of the cyclin dependent kinase inhibitor was discovered more than two decades back. It is a very famous inhibitor of CDKs and was first to be brought into the clinics for trials [4]. Alvocidib an example of pan inhibitor has been used against the patients of CLL (Chronic lymphocytic leukemia) and arthritis [5]. Pharmacokinetic and some other properties of Flavopiridol were analyzed during the clinical trial of phase I in the patients of acute leukemia [6]. As far as mode of action is concerned the inhibitor has been studied and reported to enhance the expression of Bcl-2 as well as decrease the expression of some oncogenic factors of transcription [7]. This inhibitor has been studied to be effective singly and has been used too but it can also be used with other drugs effectively in combinatorial therapy. In order to use this drug in combination with Glivec a patent has been done. This combination can be used against BCR/ABL positive leukemia cells. More studies on this drug in phase I clinical trial has revealed its role in refractory CLL where it quite efficiently controls the disease [8]. The drug has shown synergistic effects when used with Doxorubicin, Etoposide, Paclitaxel and Topotecane etc. [9]. The trials on this drug are still under process so for more efficient results schedule, pattern and timing of administration have to be monitored 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
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.
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.
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.
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.Doxorubicin (Adriamycin) HCl can be used to induce animal models of kidney disease.
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.