KINASE INHIBITORS IN CANCER THERAPY

by Selleckchem | Oct 10 2012

KINASES IN CELL SIGNALLING:
Kinases can rightly be called as the gateways of the cells due to their role in signal transduction in the cell. They function by activating or stimulating the critical pathway by phosphorylating the protein molecules. After getting stimulated enzymes allow the cells to perform some specific functions necessary for its proliferation, survival and growth etc. kinases are of many types which are Receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs) and serine/threonine kinases [1]. Mixed kinases and histidine kinases are also some of the examples of kinases. Basically kinases themselves get activated by a signaling molecule like a ligand from the extracellular environment or some other kinases and further activate subsequent molecule by phosphorylating or dephosphorylating them. Aurora kinase is an important example of kinase enzymes. Different types of agonist and antagonist molecules are used to study and unveil different functions of kinases in the cells. Kinase inhibitor is one of the examples of outcomes of such research on kinases and their inhibition [2]. Different types of kinase assays are also there to study and analyze some specific kinds of kinases [3].

INHIBITION OF KINASES:
As kinases play an important role in cell signaling their inhibition or over activation may be lethal for a cell. In many different types of cancers it is over expressed and is involved in irregulated proliferation, therefore they are an attractive target of anti-cancer drugs and protein kinase A (PKA) inhibition is an example of it [4]. Cancers may be quite reasonably treated by inhibiting different types of kinases involved in signal transduction. An over amplified pathway is inhibited by designing kinase inhibitors properly and rationally [5]. A lot of research have been and is ongoing for early treatment of diseases at cellular level in order to enhance the chances of easier treatment and to avoid late complications of the disease. Lots of inhibitors have been studied for their efficacy and pharmacokinetic properties and kinases inhibitors have been found to be the most remarkable tools to treat cancer. Imatinib mesylate, Sorafenib, Erlotinib and Gefitinib are some of the examples of kinase inhibitors [6]. Some of these are specific for specific types of kinases but mostly they are broad spectrum inhibitors. Like other drugs these inhibitors can be easily bought from the drug suppliers for any purpose like research or laboratory etc. in reasonable prices.

INHIBITON OF KINASE AND CLINICAL TRIALS:
Uptill now different types of inhibitors of kinases have been studied for their clinical efficacies. Gefitinib and Erlotinib gave efficacious results in case of breast cancer [7]. There are also some tyrosine kinase inhibitors which have been studied for their activity during different clinical trials. In addition to the inhibitors described, lots of other molecules are also being studied for cancer and tumor therapies and efficacious results have been seen. Roscovitine is another drug that showed good performance in phase I clinical trial when used against glomerulonephritis and in phase II studies against various other cancers [8]. Bevacizumab, an inhibitor of VEGF, is an anti-kinase antibody and was studied in clinical trial phase III for the treatment of colorectal and lung cancer and increase in the rate of survival was found [9]. Crizotinib or PF02341066 is a kinase inhibitor that inhibits ALK enzyme. It has been studied in clinical trial phase II against non small cell lung cancer or NSCLC [10]. Trastuzumab, another kinase inhibitor, has show potency against metastatic form of breast cancer [11].

REFERENCES:
1. Edelman AM, e.a., Protein Serine/Threonine Kinases. Annual Review of Biochemistry, 1987.
2. Hartmann JT, e.a., Tyrosine Kinase Inhibitors - A Review on Pharmacology, Metabolism and Side Effects. Current Drug Metabolism, 2009.
3. Kolb AJ, e.a., Tyrosine kinase assays adapted to homogeneous time-resolved fluorescence. Drug Discovery Today, 1998.
4. Kammer GM, e.a., The adenylate cyclase-cAMP-protein kinase A pathway and regulation of the immune response. Immunology Today, 1988.
5. Zhang J, e.a., Targeting cancer with small molecule kinase inhibitors. Nature Reviews Cancer, 2009.
6. Arora A, S.E., Role of Tyrosine Kinase Inhibitors in Cancer Therapy. JPET, 2005.
7. Agrawal A, e.a., Overview of tyrosine kinase inhibitors in clinical breast cancer. Endocr Relat Cancer, 2005.
8. Meijer L, R.E., Roscovitine and Other Purines as Kinase Inhibitors. From Starfish Oocytes to Clinical Trials. Acc. Chem. Res., 2003.
9. Jain RK, e.a., Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nature Clinical Practice Oncology, 2006.
10. Kwak EL, e.a., Anaplastic Lymphoma Kinase Inhibition in Non-Small-Cell Lung Cancer. N Engl J Med, 2010.
11. Shawver LK, e.a., Smart drugs: Tyrosine kinase inhibitors in cancer therapy. Cancer Cell, 2002.

Cat.No.	Product Name	Information
S1025	Gefitinib	Gefitinib is an EGFR inhibitor for Tyr1173, Tyr992, Tyr1173 and Tyr992 in the NR6wtEGFR and NR6W cells with IC50 of 37 nM, 37nM, 26 nM and 57 nM, respectively. Gefitinib promotes autophagy and apoptosis of lung cancer cells via blockade of the PI3K/AKT/mTOR pathway.
S1023	Erlotinib HCl	Erlotinib HCl is an EGFR inhibitor with IC50 of 2 nM in cell-free assays, >1000-fold more sensitive for EGFR than human c-Src or v-Abl.
S1068	Crizotinib	Crizotinib is a potent inhibitor of c-Met and ALK with IC50 of 11 nM and 24 nM in cell-based assays, respectively. It is also a potent ROS1 inhibitor with Ki value less than 0.025 nM. Crizotinib induces autophagy through inhibition of the STAT3 pathway in multiple lung cancer cell lines.
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.