INHIBITION OF KINASES IN CANCER THERAPY

by Selleckchem | Aug 08 2012

SIGNALING VIA KINASES:
Kinases are protein phosphorylating enzymes that function as gateways for the transmission of signals from extracellular to intracellular world of the cell. They stimulate the cells to carry out processes necessary for their survival, growth and proliferation etc. Different types of kinases are there in the cell for example; receptor tyrosine kinases, non-receptor tyrosine kinases, serine/threonine kinases [1], Histidine kinases and mixed kinases. The basic mode of action of kinases is to get activated by a signaling compound that may be a ligand or any other kinase and transmit the message to the next molecule in the form of its phosphorylation or dephosphorylation. MAP kinase is also one of the examples of such kinases. Different agonists and antagonists are there that can be used for studying the role of kinases in cell signaling. Development and production tyrosine kinase inhibitor is one of the advantages of such small compounds [2]. Kinase assays are also there that can be used for the analysis of activity of a particular kinase in specific state [3].

INHIBITION OF KINASES:
As explained above, kinases are the most important part of cell signaling pathways therefore may be an important target of anti cancer drugs e.g., protein kinase A inhibition [4]. Inhibition of kinases may be a reasonable way to check any signal transduction pathway. In case of cancer proper therapy may be devised by developing kinase inhibitors against the over-excited pathway [5]. Lots of research has been and is being done on the early control of the diseases e.g., for cancer on cellular level. Many different types of kinase inhibitors have been analyzed for their efficacy and pharmacokinetic properties after the scientists got convinced that the inhibition of tyrosine kinase may be an efficient therapy against cancer, examples of such inhibitors include; Gefitinib, Imatinib mesylate , Sorafenib and Erlotinib [6]. Most of these drugs are broad spectrum while some may be specific against kinases. Such specific inhibitors are also available commercially and can be bought for laboratory or research purpose from the suppliers of kinase inhibitors.

CLINICAL TRIALS OF KINASE INHIBITORS:
Many different kinase inhibitors have gone through clinical trials. Gefitinb and Erlotinib have shown success in clinical trials in breast cancer [7] and proved that these bayer kinase inhibitors are more efficient and popular due to successful clinical trials. In addition to these molecules many others are also being tried in clinics and many have shown efficient results in case of cancers and tumors. Roscovitin is another drug that has been used against glomerulonephritis in phase I of clinical trials and for other different cancers in clinical trial phase II [8]. Bevacizumab, VEGF inhibitor i.e., an antibody against this kinase, is being tried in clinics in phase III against colorectal cancer and lung cancer and has increased the survival rate [9]. Crizotinib or PF-02341066 is an inhibitor of ALK enzyme that is a tyrosine kinase. It has been used against non small cell lung cancer (NSCLC) in clinical trial phase II [10]. Trastuzumab, another kinase inhibitor, was proved potent against metastasizing breast cancer in preclinical studies [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.
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.
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.
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.
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.