Nilotinib, Hydrochloride Salt, Monohydrate

Soluble in DMSO. Nilotinib, a novel, selective BCR-ABL inhibitor, fits into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. Nilotinib is not only more potent than imatinib against wild-type BCR-ABL (IC50 < 30 nM), but also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. Weisberg, E., et al. 'AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL.' Br. J. Cancer 94: 1765-1769 (2006). Nilotinib inhibited the proliferation of haematopoietic cells expressing the mutations in Ph+ chronic myelogenous leukemia (CML) and acute lymphoblastic leukaemia with IC50's of ~ 12 nM, thus being more potent than imatinib. Nilotinib was also effective against several imatinib-resistant Bcr-Abl mutants, but not T315I. Weisberg, E., et al. 'Characterization of AMN-107, a selective inhibitor of native and mutant Bcr-Abl.' Cancer Cell. 7: 129-141 (2005). Nilotinib and dasatinib are respectively 20-fold (IC50: 15 nM versus 280 nM) and 325-fold (IC50: 0.6 nM versus 280 nM) more potent than imatinib against cells expressing wild-type Bcr-Abl. Similar improvements are also seen in all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors have activity against imatinib-refractory CML. O'Hare, T., et al. 'In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.' Cancer Res. 65: 4500-4505 (2005). The effects of nilotinib were studied on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0) and were compared with those of imatinib. The antiproliferative activity of nilotinib was 43 times more potent than that of imatinib in KBM5 cells (IC50 of 11 nM versus 480 nM) and 60 times more potent in KBM7 cells (IC50 of 4 nM versus 259 nM). IC50's for nilotinib were 2.4 µM in KBM5-STI571R1.0 and 97 nM in KBM7-STI571R1.0 cells, while IC50's for imatinib were 6.4 µM in KBM5-STI571R1.0 and 2.5 µM in KBM7-STI571R1.0 cells. Golemovic, M., et al. 'AMN107, a Novel Aminopyrimidine Inhibitor of Bcr-Abl, Has In vitro Activity against Imatinib-Resistant Chronic Myeloid Leukemia.' Clin. Cancer Res. 11: 4941-4947 (2005). Nilotinib was as potent as imatinib in inducing apoptosis (IC50 = 0.54 nM) and inhibiting proliferation (IC50 = 0.20 nM) of EOL-1 cells. Verstovsek, S., et al. 'Activity of AMN107, a novel aminopyrimidine tyrosine kinase inhibitor, against human FIP1L1-PDGFR-alpha-expressing cells.' Leuk. Res. 30: 1499-1505 (2006). Nilotinib is under investigation as a possible treatment for the patients with chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial showed nilotinib to have a relatively favorable safety profile and to display activity in patients with CML resistant to treatment with imatinib (Gleevec(R)).