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NILOTINIB

CHRONIC MYELOGENOUS LEUKEMIA AND PHILADELPHIA CHROMOSOME

During meiosis if BCR and tyrosine kinase ABL are unable to separate and fuse together it leads to condition called Philadelphia chromosome. Due to the fusion of these genes it leads to translation of abnormal protein which acts as malfunctioned tyrosine kinase that makes it oncoprotein. Around 90% of patients suffering from Ph+ also suffer from chronic myelogenous leukemia or CML. This fusion protein is being targeted for therapy of cancer since it is involved in CML and various researches are being carried out in this regard. An inhibitor of this protein is Nilotinib bcr-abl inhibitor which is used to treat CML.


PROPERTIES OF NILOTINIB AND ITS MODE OF ACTION

Novartis has developed Nilotinib AMN-107 for treatment of ALL and CML patients who were also having Philadelphia chromosome. Hydorchloride monohydrate and benzamide group was found in Nilotinib structure. Nilotinib solubility is found to be 50mg/ml of DMSO while it is insoluble in ethanol and water. For inhibition of BCR-ABL Nilotinib IC50 is found to be less than 12nM however it is beyond 12nM for PDGF and c-kit. It is marketed at the rate of $60 per 400mg of vial. Its price varies among different suppliers and Nilotinib supplier supply it to researchers/scientists who want to buy Nilotinib.
To improve the efficacy of Nilotinib research is being carried out on modification of its structure [1]. Structural studies showed that Nilotinib inhibits tyrosine kinase by binding at its ATP site and thereby blocks the downstream pathway that is involved in cell proliferation.  Resistant patients showed more specific results [2]. In genes of Ph+ patients point mutations are found against this medicine [3]. The properties like more stability and less toxicity makes it most favourable among the former medicines which are being used for treatment of CML these medicines include Dasatinib and Imatinib [4]. The differences in the chemical structure of Nilotinib and that of Dasatinib and Imatinib make Nilotinib more efficient [5].In new research study is being made on NK cells against these three medicines [6].


CLINICAL TRIALS OF NILOTINIB

Clinical trials of Nilotinib have been carried out on CML as well as GISTs patients. Most of the trials are been carried on Ph+ CML and ALL patients who were resilient to Imatinib [7]. So clinical trials of phase I & II are being conducted on patients suffering from chronic myelogenous leukaemia [8-10] and hence promising results were shown by it in clinical trials [11]. Based on successful results its phase III trials are being conducted [12]. In phase III not only old CML patients but also freshly diagnosed patients were also studied [13].

This medicine has also been used in GISTs patients after its outstanding results in CML patients in phase III trials [14]. Recent research is being done by Novartis on patients of chronic myelogenous leukaemia in phase II and on GISTs patients in phase III. The fruitful results shown this medicine ensures its promising future in the field of cancer therapy.

 

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.

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Cat.No. Product Name Information Publications Customer Product Validation
S1033 Nilotinib (AMN-107) Nilotinib (AMN-107) is a selective Bcr-Abl inhibitor with IC50 less than 30 nM in Murine myeloid progenitor cells. Nilotinib induces autophagy through AMPK activition. (112) (5)
S1021 Dasatinib (BMS-354825) Dasatinib (BMS-354825) is a novel, potent and multi-targeted inhibitor that targets Abl, Src and c-Kit, with IC50 of <1 nM, 0.8 nM and 79 nM in cell-free assays, respectively. Dasatinib induces autophagy and apoptosis with anti-tumor activity. (423) (13)
S1026 Imatinib (STI571) Mesylate Imatinib (STI571, CGP057148B, Gleevec) 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. (182) (6)

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