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Imatinib, Nilotinib, Paclitaxel and to help them make more significant discoveries.">Nilotinib (AMN107) is a tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia (CML). Constitutively active tyrosine kinase bcr-abl is responsible for causing chronic myeloid leukemia. Nilotinib is a multikinase inhibitor targeting a variety of kinases including bcr-abl, c-kit, platelet-derived growth factor (PDGF-R), EPHA3, EPHA8, DDR1, DDR2, MAPK11, ZAK etc. It is also called a second generation drug for cancer, imatinib being the first. The drug has gained popularity owing to its efficacy in the treatment of imatinib reisiatnt patients. Imatinib is the first generation drug for the treatment of cancer that brought reveloution in the pharmaceutical industry after its approval in 2003. Imatinib is a tyrosine kinase inhibitor and specifically inhibits tyrosine kinase domain in abl, c-kit and PDGF-R kinases. In chronic myeloid leukemia, a fusion protein of abl is formed with bcr which makes it constitutively active tyrosine kinase leading to cancerous cell proliferation. As shown in the figure, the bcr-abl has a small pocket where ATP can bind. Phosphate group from ATP is transferred to the substrate which then stimulates the effector molecules for downstream signaling. Imatinib acts as an inhibitor by occupying this bcr-abl site. ATP cannot bind in the presence of imatinib and downstream signaling is inhibited. Imatinib was reported to be an efficient inhibitor but cases of resistance to this drug started to appear which led the scientist towards the quest of even better inhibitors. Resistance to tyrosine kinase inhibitors may be due to the drug efflux (A), binding of drug to some plasma protein (B), mutations in bcr-abl domains (C), activation of downstream pathways like those of Src family (D) or abnormal bcr-abl gene amplifications. Clinical administration of nilotinib to the imatinib resistant patients produced very encouraging results. Nilotinib is an analog of imatinib with similar mutikinase targets and both bind to inactive conformation of bcr-abl. However, nilotinib does not inhibit Src gene. Binding of Nilotinib with the bcr-abl is energetically more favorable than imatinib. Nilotinib can bind the target more selectively which increases its ability to inhibit tumour proliferation far more than imatinib. Also, some mutations in abl kinase domain are the source of resistance to imatinib. Nilotinib has been designed after considering those mutations, so that it can bind mutant domains as well. It has been approved as second generation drug in 2007. Epidemiological studies show that the risk of cancer is increased in diabetic patients. It has been observed that careful administration of some anticancer agents including nilotinib, certainly increases life expectancy in these patients. The biochemical analysis show that IGF-1 (insulin like growth factor-1) signaling pathway involves a tyrosine kinase; c-abl and this signaling modulates the mitogenic and metabolic activity as shown in the figure. In the presence of nilotinib, there is decreased metabolic activity on insulin stimulation. Conclusion It can be concluded that nilotinib is a highly beneficial advantage in the list of compounds in chemical libraries. Importance of imatinib cannot be declined as well. It is still used as the first line drug for treating chronic myeloid leukemia. However, the patients showing resistance to imatinib are referred to the use of nilotinib. This also potentiates the need of virtual screening and computational approaches to design newer and better libraries for the compounds against which resistance has developed. This can lead to tremendous success stories in the field of drug discovery! To meet customers's needs and satisfaction, our purpose is to provide scientists world-wide an easy access to the most innovative life science reagents like Imatinib, Nilotinib, Paclitaxel and to help them make more significant discoveries.
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