Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A et al.. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 7: 129-141

Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Cancer Cell (Impact Factor: 23.52). 03/2005; 7(2):129-41. DOI: 10.1016/j.ccr.2005.01.007
Source: PubMed


The Bcr-Abl tyrosine kinase oncogene causes chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). We describe a novel selective inhibitor of Bcr-Abl, AMN107 (IC50 <30 nM), which is significantly more potent than imatinib, and active against a number of imatinib-resistant Bcr-Abl mutants. Crystallographic analysis of Abl-AMN107 complexes provides a structural explanation for the differential activity of AMN107 and imatinib against imatinib-resistant Bcr-Abl. Consistent with its in vitro and pharmacokinetic profile, AMN107 prolonged survival of mice injected with Bcr-Abl-transformed hematopoietic cell lines or primary marrow cells, and prolonged survival in imatinib-resistant CML mouse models. AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL.

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    • "Nilotinib (Tasigna, known as AMN107; Novartis Pharma AG) is a second-generation TKI that is expected to show enhanced clinical efficacy against GIST. Nilotinib is a potent TKI that has been shown both in vitro and in vivo to inhibit the auto-phosphorylation and proliferation of cells transformed with activating mutations of KIT or platelet-derived growth factor receptor-alpha (PDGFRA) tyrosine kinases, which are the kinases that are the key oncogenic drivers in GIST [7]–[9]. Imatinib resistance poses a significant challenge in the clinical management of GIST. "
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    • "All clinically reported compound mutations (100%) in Figure 1 include a key position, and the majority (65%) involve two (Figures 1B and 1C). Each position has been implicated in resistance to one or more TKIs: imatinib (Bradeen et al., 2006; Gorre et al., 2001), nilotinib (Bradeen et al., 2006; Ray et al., 2007; Weisberg et al., 2005), dasatinib (Bradeen et al., 2006; Burgess et al., 2005; Shah et al., 2004), bosutinib (Redaelli et al., 2009), ponatinib (O'Hare et al., 2009), and rebastinib (Chan et al., 2011; Eide et al., 2011). The key residues in native BCR-ABL1 are: M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396 (Figure 1A). "
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    • "The second-generation BCR-ABL kinase inhibitor, dasatinib, binds to BCR-ABL with less stringent conformational requirements and was shown to be effective in inhibition of imatinib-resistant mutants.24 Nilotinib is another second-generation BCR-ABL inhibitor and is significantly more potent than imatinib, and also has activity against a number of imatinib-resistant BCR-ABL mutants.25 Compared with imatinib, nilotinib is associated with a reduced incidence of BCR-ABL mutations in patients with newly diagnosed CML in chronic phase.26 "
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