BCR (break-point cluster) and (ABL) Abelson genes code for the protein tyrosine kinases that are involved in signal transduction fusion of these two genes occur when a philadalphia chromosome is formed after some mistake in the process of crossing over. This chimeric oncogene is known as BCR-ABL and is known to be involved in the development of leukemia especially (CML) Chronic Myelogenous Leukemia. This type of fusion is known to be responsible for almost 90% CML cases and is known as PH+ CML. The participation of BCR-ABL in PH+ CML has urged the scientists to inhibit this fusion protein. Different types of inhibitors targeting this oncogenic fusion protein have been registered. Nilotinib Src-bcr-Abl inhibitor is one of such inhibitors against CML.

Nilotinib, manufactured by Novartis, has proved a very effective drug against PH+ ALL and CML. This is traded by the name Tasigna and it is orally administered in the form of 400 mg tablet. Researchers can also buy Nilotinib for their research purposes too because of its reasonable price. This price can vary from Nilotinib supplier to supplier. IC50 value for Nilotinib for an efficient Tyrosine kinase fusion oncoprotein inhibition is <12 nM and for PDGF and c-Kit inhibition is higher. As far as structure of Nilotinib is concerned, it contains a benzamide group. It is poorly soluble in ethanol and water and is soluble upto 50mg/ mL in DMSO.
Initially chemical modification and characterization of Nilotinib had been done in order to improve its specificity keeping its inhibitory effect intact [1]. Nilotinib binds to the ATP binding sites of Tyrosine kinases and keep them inactive. Identification of some point mutations in some patients after genetic screening has been known to cause resistance in these patients against Nilotinib [2]. These mutations have made this tyrosine kinase inhibitor more patient specific [3].
Nilotinib has a low toxicity profile and good stability due to which it is considered more effective as compared to the traditional drugs used in CML therapy for example Dasatinib and Imatinib [4].  The research on the chemical and structural differences of the drugs used against CML has made it possible to develop extremely effective and specific drug hence three inhibitors has been observed in Natural Killer cells [6].

Resistance against drugs is a universal phenomenon which keeps researches busy in developing alternatives to these drugs. Nilotinib has been tested on patients of PH+ ALL and CML who are resistant against Imatinib [7]. The drug has successfully gone through the clinical trial phase I. Now in clinical trial phase II it is being tested in patients of chronic CML who are resistant or intolerant against Imatinib [8-10]. The drug has proved a success for treatment against phase II patients of PH+ CML [11], and is being tested for phase III trials for the same type of PH+ CML patients [12]. Nilotinib is not only effective against advanced phase patients but is also favored over Imatinib for initial phases of CML [13].

In case of GIST i.e., gastrointestinal stromal tumors the Nilotinib has been studied in Phase I –III trials and has been proved effective [14]. At present Novartis, the drug manufacturing company is conducting clinical trials of Nilotinib for both the CML and GIST patients. For CML it is in clinical Phase II clinical trials (NCT00129740) and for GIST it is in Phase III of clinical trials open label clinical trials (ENESTg1) (NCT00785785).

1. Weisberg, E.e.a., AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. British Journal of Cancer, 2006. 94: p. 1765-1769.
2. Bubnoff, N.V.e.a., BCR-ABL resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor Nilotinib (AMN107). Blood, 2006. 108: p. 1328-1333.
3. Ray, A.e.a., Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study. Blood, 2007. 109(11): p. 5011-5015.
4. Bradeen, H.A.e.a., Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)–based mutagenesis screen: high efficacy of drug combinations. Blood, 2006. 108: p. 2332-2338.
5. Rix, U.e.a., Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood, 2007. 110(12): p. 4055-4063.
6. Salih, J.e.a., The BCR/ABL-inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity. Int J Cancer, 2010. 127(9): p. 2119-28.
7. Kantarjian, H.e.a., Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med., 2006. 354(24): p. 2542-51.
8. Kantarjian, H.e.a., Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood, 2011. 117(4): p. 1141-1145.
9. Kantarjian, H.e.a., Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood, 2007. 110(10): p. 3540-3546.
10. Coutre, P.L.e.a., Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood, 2008. 111(4): p. 1834-1839.
11. Rosti, G.e.a., Nilotinib for the frontline treatment of Ph+ chronic myeloid leukemia. Blood, 2009. 114(24): p. 4933-4938.
12. Kantarjian, H.M.e.a., Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. The Lancet Oncology, 2011. 12(9): p. 841-851.
13. Saglio, G.e.a., Nilotinib versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia. N Engl J Med, 2010. 362: p. 2251-2259.
14. Reichardt, P.a.M., M., Clinical Experience to Date With Nilotinib in Gastrointestinal Stromal Tumors. Seminars in Oncology, 2011. 38(1): p. S20-S27.


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