KINASES INHIBITION FOR CANCER THERAPY

by Selleckchem | Sep 24 2012

SIGNALING THROUGH KINASES:
Kinase enzymes are the protein phosphorylating enzymes which act as gateways for the transmission of metabolic signals from the extracellular to intracellular environment of the cell. Kinases stimulate the cells to perform the processes which are necessary for the cell survival, proliferation and cell growth etc. Many types of kinase enzymes exist in the cells like serine/threonine kinases, receptor tyrosine kinases and non-receptor tyrosine kinases [1], Histidine kinases and the mixed kinases. Basic mechanism of action of kinase proteins is to aquire activated state by some sort of signaling compound that can be a special ligand or some other kind of kinase and send the stimulus to the subsequent molecule in form of its dephosphorylation or phosphorylation. One of the important examples of such kinases is p38 MAP kinase. Various antagonists and agonists are there which can be utilized for studying the function of kinases in the signaling of cell. One of the main advantages of such type of small compounds is the production and development of bayer kinase inhibitor [2]. For the analysis and study of the activity of a particular kind of kinase in some specific, the Kinase assays are being used [3].

KINASE INHIBITION:
As described above, kinase enzymes are one of the most important component of cell signaling cascades hence may be an attractive target for the anti-cancer drugs for example inhibition of protein kinase A [4]. The inhibition of kinase proteins may be a very reasonable method for checking a signal transduction pathway. A proper way of therapy may be designed in the case of cancers, by designing kinase inhibiting drugs against over exited cascade [5]. Great research has been done and also being done on the control of diseases at early stages like for cancer on the cellular level. Various kinds of kinase inhibitors have been studied due to their pharmacokinetic properties and efficacy and after that scientists got influenced form the idea that inhibition of tyrosine kinase enzyme may be a remarkable therapeutic tool against the cancer. The examples for such inhibiting drugs include Imatinib mesylate, Erlotinib, Sorafenib and Gefitinib [6]. Among these drugs most are broad spectrum but some are very specific against specific kind of kinases. These specific inhibitors are easily commercially available as well and the researchers can bought easily for their research and laboratory purposes from the respective suppliers of these kinase inhibitors.

KINASE INHIBITORS IN CLINICAL TRIALS:
Various kinds of kinase inhibitors have undergone through the clinical studies. Erlotinib and Gefitinib even have shown remarkable success in their trials against breast cancer [7] hence proved that such serine threonine kinase inhibitors are more popular and efficient due to their successful clinical studies. Many other molecules in addition to these are also being tested in the clinical trials and many of them have exhibited good promising results in case of tumors and cancers. Another drug named Roscovitine has been analyzed in clinical trials phase I against glomerulonephritis and also against other various cancers in clinical testing phase II [8]. A VEGF inhibitor named Bevacizumab that is an antibody for kinase, was tried in phase III clinical trials against lung cancer and colorectal cancer and has found to cause an increase in rate of cell survival [9]. An inhibitor of ALK enzyme named PF-02341066 or Crizotinib is a tyrosine kinase. This inhibitor has been used to treat NSCLC or non small cell lung cancer in phase II clinical trial [10]. Another kinase inhibitor is Trastuzumab which was proved a potent drug against in preclinical trials against metastasizing 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
S1026	Imatinib Mesylate	Imatinib Mesylate is an orally bioavailability mesylate salt of Imatinib, which is a multi-target inhibitor of v-Abl, c-Kit and PDGFR with IC50 of 0.6 μM, 0.1 μM and 0.1 μM in cell-free or cell-based assays, respectively. Imatinib Mesylate (STI571) induces autophagy.
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.
S1040	Sorafenib tosylate	Sorafenib tosylate is a multikinase inhibitor of Raf-1 and B-Raf with IC50 of 6 nM and 22 nM in cell-free assays, respectively. Sorafenib Tosylate inhibits VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-KIT with IC50 of 90 nM, 20 nM, 57 nM, 59 nM and 68 nM, respectively. Sorafenib Tosylate induces autophagy and apoptosis and activates ferroptosis with anti-tumor activity.
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.
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.
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.