AMN107 (nilotinib): a novel and selective inhibitor for BCR-ABL

Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA.
British Journal of Cancer (Impact Factor: 4.84). 06/2006; 94(12):1765-9. DOI: 10.1038/sj.bjc.6603170
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Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) are caused by the BCR-ABL oncogene. Imatinib inhibits the tyrosine kinase activity of the BCR-ABL protein and is an effective, frontline therapy for chronic-phase CML. However, accelerated or blast-crisis phase CML patients and Ph+ ALL patients often relapse due to drug resistance resulting from the emergence of imatinib-resistant point mutations within the BCR-ABL tyrosine kinase domain. This has stimulated the development of new kinase inhibitors that are able to over-ride resistance to imatinib. The novel, selective BCR-ABL inhibitor, AMN107, was designed to fit into the ATP-binding site of the BCR-ABL protein with higher affinity than imatinib. In addition to being more potent than imatinib (IC50< 30 nM) against wild-type BCR-ABL, AMN107 is also significantly active against 32/33 imatinib-resistant BCR-ABL mutants. In preclinical studies, AMN107 demonstrated activity in vitro and in vivo against wild-type and imatinib-resistant BCR-ABL-expressing cells. In phase I/II clinical trials, AMN107 has produced haematological and cytogenetic responses in CML patients, who either did not initially respond to imatinib or developed imatinib resistance. Dasatinib (BMS-354825), which inhibits Abl and Src family kinases, is another promising new clinical candidate for CML that has shown good efficacy in CML patients. In this review, the early characterisation and development of AMN107 is discussed, as is the current status of AMN107 in clinical trials for imatinib-resistant CML and Ph+ ALL. Future trends investigating prediction of mechanisms of resistance to AMN107, and how and where AMN107 is expected to fit into the overall picture for treatment of early-phase CML and imatinib-refractory and late-stage disease are discussed.

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    • "Nilotinib is a new generation of oral tyrosine kinase inhibitor used for the treatment of gastrointestinal stromal tumors and for newly diagnosed chronic myeloid leukemia or for patients presenting resistance or intolerance to imatinib [72]. In addition, it also has 20–50 times greater inhibitory activity against the PDGF-R and c-Kit kinases than imatinib [73]. In a monocrotaline rat model of pulmonary hypertension, nilotinib reduced right ventricular pressure and percentage of muscularized lung vessels with efficacy similar to that of imatinib [74]. "
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    BioMed Research International 06/2014; 2014(2):743868. DOI:10.1155/2014/743868 · 2.71 Impact Factor
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    • "Exploration of alternative and additional therapeutic tools, particularly drugs that can exert anti-PD effects without direct activation of dopamine receptors, is therefore prudent . In this study, we provide a novel finding that in MPTP mice, striatal motor behaviors were normalized by systemic administration of nilotinib, a drug that is now clinically used to treat chronic myeloid leukemia (Weisberg et al., 2006; Blay and von Mehren, 2011). Together with the reported experimental findings that nilotinib (Hebron et al., 2013) and other c-Abl inhibitors (Ko et al., 2010; Imam et al., 2011, 2013) also play a protective role against the neurodegeneration of dopamine-producing cells in the substantia nigra of mice, our results suggest that nilotinib may serve as an alternative agent for attenuating motor symptoms and disease progression of PD. "
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    ABSTRACT: Abnormal motor behaviors in Parkinson's disease (PD) result from striatal dysfunction due to an imbalance between dopamine and glutamate transmissions that are integrated by dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32). c-Abelson tyrosine kinase (c-Abl) phosphorylates cyclin-dependent kinase 5 (Cdk5) at Tyr15 to increase the activity of Cdk5, which reduces the efficacy of dopaminergic signaling by phosphorylating DARPP-32 at Thr75 in the striatum. Here, we report that in the mouse striatum, a novel c-Abl inhibitor, nilotinib (AMN107), inhibits phosphorylation of both Cdk5 at Tyr15 and DARPP-32 at Thr75, which is negatively regulated by dopamine receptor activation through a D2 receptor-mediated mechanism. Like a D2-agonist, nilotinib synergizes with a D1-agonist for inducing striatal c-Fos expression. Moreover, systemic administration of nilotinib normalizes striatal motor behaviors in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings suggest that nilotinib could possibly serve as a new and alternative agent for treating PD motor symptoms.
    Frontiers in Cellular Neuroscience 02/2014; 8:50. DOI:10.3389/fncel.2014.00050 · 4.29 Impact Factor
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    • "Regardless of its outstanding results in chronic phase of CML, appearance of drug resistant cells and disease relapse lead to a new way of research in field of protein tyrosine kinase inhibitor design and development. Accordingly new generation of protein tyrosine kinase inhibitors (nilotinib, dasatinib, busotinib and ponatinib) are evolved with more potency against active form of BCR–ABL fusion protein [10] [11] [12] [13]. Although, multidrug resistance (MDR) still exists as a major clinical problem in cancer chemotherapy which causes decrement of drug efficacy and increment of disease relapse [14]. "
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