NILOTINIB AND PHILADELPHIA

by Selleckchem | Jul 25 2012

CML AND PHILADELPHIA CHROMOSOME
During meiosis the fusion of two genes including BCR a breakpoint cluster and ABL tyrosine kinase results in the formation of Philadelphia chromosome. The resultant fusion protein expressed due to Philadelphia chromosome is not controlled and function abnormally leading to an oncoprotein. Chronic myelogenous leukemia or CML is caused by this fusion oncoprotein in 90% of the patients of CML. Due to huge part of this protein in CML, in drug development for cancer treatment this protein is being targeted by researchers by the help of small molecule screening. Nilotinib AMN-107 is one of the inhibitor used for this purpose to cure CML.

NILOTINIB MECHANISM OF ACTION AND PROPERTIES:
Nilotinib is among bcr-Abl inhibitors was developed by Novartis and used for ALL and CML patients who are Ph+. Nilotinib solubility is good in DMSO that is upto 50 mg/ml but it is poorly soluble in ethanol and water. Nilotinib structure is based in a salt of hydrochloride monohydrate and also contains a benzamide group in it. For c-Kit and PDGF the Nilotinib IC50 is more than 12nM but for BCR-ABL inhibition it is less than 12nM. The trade name of Nilotinib is Tasigna and it is available in the form of a 400 mg tablet that is orally administered. If someone wants to buy Nilotinib one can order Nilotinib to any of the Nilotinib supplier by paying $60 for a 100mg packet however this price is variable.
The efficacy is being enhanced by modifying Nilotinib’s structure which is also under research [1]. Nilotinib is an inhibitor of tyrosine kinase because it binds with ATP binding site and ultimately it prevents the downstream cascade which is important for cell growth and proliferation. In specific patients the resistance against Nilotinib has been developed but mostly it is effective drug [2]. The resistance against this agent has been noticed due to some point mutations is Ph+ patients [3] even then Nilotinib is better than other drugs which were used against CML for example Imatinib and Dasatinib, the superiority is based on stability and less toxicity [4]. There are also some chemical differences in these both drugs and Nilotinib which define even more development of this therapeutic agent [5]. Recently in a differential manner the action of three drugs is under studies on natural killer (NK) cells [6].

NILOTINIB CLINICAL TRIALS STUDIES:
After screening of drug library, Nilotinib clinical trials are in process on CML and GISTs patients. It is frequently used for Ph+ ALL and CML patients having resistance against Imatinib [7]. The action of Nilotinib on chronic CML patients is being evaluated during clinical phase I and II [8-10]. During initial clinical trials it was having remarkable results [11] due to which it is now promoted to clinical trials phase III for CML Ph+ patients [12].
Being successful in the initial phases of clinical trials [11], it has been promoted to phase III clinical trials in Ph+ CML patients [12]. Nilotinib is not only studied against chronic CML patients but it has also shown good results in newly diagnosed CML patients in clinical trial phase III [13]. With a lot of success when used on CML patients, Nilotinib is also being used for the treatment of GIST or gastrointestinal stromal tumors, and these findings also reported as efficient results during phase III trials [14]. In present Novartis is carrying study on patients of GIST during phase II and during phase III open label studies on patients GISTs (ENESTg1) (NCT00785785) is going on. Keeping all the properties of Nilotinib this is considered as a leading edge therapeutic for cancer treatment.

REFERENCES:
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. 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.
3. 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.
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.

Cat.No.	Product Name	Information
S1033	Nilotinib	Nilotinib is a selective Bcr-Abl inhibitor with IC50 less than 30 nM in Murine myeloid progenitor cells. Nilotinib induces autophagy through AMPK activition.
S2475	Imatinib	Imatinib is a multi-target inhibitor of tyrosine kinase with inhibition for v-Abl, c-Kit and PDGFR, IC50 values are 0.6 μM, 0.1 μM and 0.1 μM in cell-free or cell-based assays, respectively. Imatinib (STI571) induces autophagy.