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: 23.89). 03/2005; 7(2):129-41. DOI: 10.1016/j.ccr.2005.01.007
Source: PubMed

ABSTRACT 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, Aug 25, 2015
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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.
    Cancer Cell 08/2014; 26(3). DOI:10.1016/j.ccr.2014.07.006. · 23.89 Impact Factor
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    • "Nilotinib has been established as a drug with potency superior to that of imatinib as an inhibitor of BCR-ABL. Nilotinib also inhibits the tyrosine kinase activity of the PDGF and c-KIT receptors DDR1 and DDR2 with efficacy similar that of imatinib [20] [21]. The mammalian target of rapamycin (mTOR), a serine/threonine kinase, integrates multiple signaling pathways, including those that control growth and survival of tumor cells and angiogenesis. "
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    • "Med Chem Res (2014) 23:2622–2632 DOI 10.1007/s00044-013-0852-5 MEDICINAL CHEMISTRY RESEARCH (Parke-Davis) potently inhibits the autophosphorylation of p210 Bcr-Abl and induces apoptosis of blast crisis cell lines (La Rosee et al., 2002; Wisniewski et al., 2002). Nilotinib (AMN107, Novartis) is a high affinity inhibitor that targets many imatinib resistant mutants of Bcr-Abl (Weisberg et al., 2005). Recently, VX-680 (Vertex) aurokinase inhibitor demonstrates the ability to recognize and bind to an active conformation of Abl which effectively blocks Thr315 mutation (Harrington et al., 2004; Juan, 2007). "
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    ABSTRACT: In the present investigation, structurally different compounds possessing Bcr/Abl kinase inhibitory activity and antiproliferative activity against K562 cell lines were used for the structural analysis. The significant QSAR models developed were validated by internal and external validation techniques. The contributed descriptors explain that the hydrophobic and polar properties on the van der Waals surface of the molecules determine the activities of the molecules. The correlations developed between the TPSA, logP and activities showed that the compounds have increased TPSA values possessed better Bcr/Abl kinase inhibitory activity, while those compounds have moderate logP values. Higher logP values containing compounds have less Bcr/Abl kinase inhibitory activity and moderate antiproliferative activity on K562 cancer cell lines.
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