KINASE INHIBITORS AND CANCER THERAPY

by Selleckchem | Aug 23 2012

KINASE-DOWNSTREAM SIGNALING:
Kinases act as windows for cells to the outer world, these enzymes are triggered by the signals coming from other cells, stimuli from the environment and as a result these kinases carry out phosphorylaiton of various molecules to transmit downstream signals. There are many types of kinase enzymes such as pim kinase and out of these most common are protein kinases. These protein kinases can also be further subdivided into various categories like receptor tyrosine kinase enzyme, threonine/serine protein kinases [1], mixed kinases and histidine protein kinases. Many of the kinase agonists and kinase antagonists have been employed for the understanding of multiple cellular pathways during research under physiological environment. Reviews on kinase inhibitors can prove the importance of these small compounds [2]. There are various kinase assays are available which can be used for the activity assessment of a kinase enzyme in a given state [3].

KINASE INHIBITORS AND KINASE INHIBTION:
Kinases are amongst the most vital enzymes of cell signaling and hence the idea of their inhibition targets some pathways in cancer for example pathway of protein kinase-A [4] a reasonable approach to check any pathway is the use of kinase inhibitor. A promising approach is the development of kinase inhibitors for the proper cancer therapy by checking downstream signaling of kinases [5]. Various research studies have proven the use of kinase inhibitors study for the inhibition of signaling pathways and early control of diseases like cancer at cellular level. In past during research studies the findings of tyrosine kinase inhibition and cancer convinced the researcher to analyze the efficiency of various inhibitor molecules like Gefitinib, Erlotinib, Sorafenib and Imatinib mesylate against cancer [6]. Many of these are broad spectrum and some are specific against kinases enzymes. Many of the specific inhibitors are commercially available for research and laboratory purposes and one can buy these inhibitors from any of the kinase inhibitor supplier.

KINASE INHIBITORS IN CLINICS:
In breast cancer patients both Erlotinib and Gefitinb have performed well [7] and these specific EGFR tyrosine kinase inhibitors have gained even more popularity due to their success in clinical trials. Various other molecules are also undergoing clinical trials and showing promising results against tumors and cancers. Roscovitin is another such inhibitor which showed efficient results during clinical trials phase I against glomerulonephritis and other cancers suring phase II of clinical trials [8]. Another VEGF-specific antibody inhibitor is Bevacizumab which produced results by increasing survival rates in patients of lung and colorectal cancers during clinical phase III trials [9]. Another inhibitor known as PF-02341066 and Crizotinib, a strong inhibitor of ALK tyrosine kinase enzyme, which lead to NSCLC (non small cell lung cancer) treatment during phase II evaluations [10]. Trastuzumab was also administered for the metastatic breast cancer therapy and proved to be potent after 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.
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.
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.
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.
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.