nilotinib brands

Molecular formula: C28H22F3N7O

Chronic myelogenous leukaemia (CML) is caused by the BCR-ABL oncogene. Nilotinib inhibits the tyrosine kinase activity of the BCR-ABL protein. Nilotinib fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib, over-riding resistance caused by mutations. The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005; Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours (Weisberg et al, 2005; von Bubnoff et al, 2005; Gleixner et al, 2006). Nilotinib, an inhibitor of Bcr-Abl tyrosine kinase, is an antineoplastic agent. Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of hematopoietic cells carrying the Philadelphia chromosome (Ph), resulting from a reciprocal translocation of the long arms of chromosomes 9 and 22. A novel fusion gene is formed, Bcr-Abl, which encodes a constitutively active, cytoplasmic form of protein tyrosine kinase. The unregulated activity of the Abl tyrosine kinase in Bcr-Abl is the cause of CML. Nilotinib is an orally active aminopyrimidine-derivative tyrosine kinase inhibitor that functions through competitive inhibition at the ATP-binding site of Bcr-Abl, leading to the inhibition of tyrosine phosphorylation of proteins that are involved in the intracellular signal transduction that Bcr-Abl mediates. Clinical resistance to imatinib in CML has been attributed to several mechanisms, but point mutations in the Bcr-Abl kinase domain appear to the most common, occurring in 30-90% of patients who develop resistance. The ability of nilotinib to overcome imatinib resistance resulting from Bcr-Abl kinase domain mutations has been demonstrated in vitro. In preclinical studies in cell-line models, nilotinib inhibited most (32 of 33) imatinib-resistant Bcr-Abl kinase domain mutant forms. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Ph+ CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM), c-Kit (210 nM), CSF-1R (125-250 nM) and DDR (3.7 nM). It is an important challenge to better understand the mechanisms of tyrosine kinase inhibitors-induced apoptosis in CML cells. Thus, /the authors/ have investigated how this apoptosis can be modulated by extracellular factors. Apoptosis induced by imatinib and nilotinib was determined in BCR-ABL expressing cell lines and primary CML CD34+ cells. Both molecules induced apoptosis of BCR-ABL expressing cells. This apoptosis was inhibited by protein synthesis inhibition in both K562 and CML CD34+ cells. In K562, 80% inhibition of the BCR-ABL auto-phosphorylation by either imatinib or nilotinib induced a two fold increase in Bim-EL expression and induction of apoptosis in 48 hr. Bim accumulation preceded apoptosis induction which was completely abolished by depletion in Bim using shRNA. However, the anti-proliferative effect of imatinib was preserved in Bim-depleted cells. When K562 cells were cultured in a cytokine containing medium, the pro-apoptotic effect of nilotinib was decreased by 68% and this was related t

Source: PubChem (NCBI) · compound 644241