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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Available from: Mohammad Azam
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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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    ABSTRACT: Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST.
    Full-text · Article · Sep 2014 · PLoS ONE
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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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    ABSTRACT: Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1T315I mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
    Full-text · Article · Aug 2014 · Cancer Cell
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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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    ABSTRACT: In a significant proportion of patients with chronic myeloid leukemia, resistance to BCR-ABL tyrosine kinase inhibitors develops due to acquisition of BCR-ABL kinase domain mutations and insensitivity of leukemia stem cells to tyrosine kinase inhibitors. Omacetaxine mepesuccinate (formerly called homoharringtonine) is a natural alkaloid that inhibits protein synthesis and induces cell death. Omacetaxine mepesuccinate has been recently approved by the US Food and Drug Administration to treat patients with chronic myeloid leukemia who failed to respond to multiple tyrosine kinase inhibitors and/or acquired the BCR-ABL-T315I mutation. In this review, we discuss the use and effectiveness of omacetaxine mepesuccinate in the treatment of chronic myeloid leukemia, with coverage of its pharmacology, mode of action, and pharmacokinetics. We believe that omacetaxine mepesuccinate will be beneficial to many patients with chronic myeloid leukemia who do not respond well to tyrosine kinase inhibitors.
    Full-text · Article · Jan 2014 · OncoTargets and Therapy
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