The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107

Bubnoff, Nikolas von; Gorantla, Saritha; Kancha, Rama Krishna; Lordick, Florian; Peschel, Christian; Duyster, Justus

doi:10.1038/sj.leu.2403887

Cited by 63 publications

(39 citation statements)

References 8 publications

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“…The ability of AMN107 to inhibit TEL-platelet-derived growth factor receptor-beta (TEL-PDGFRbeta), which causes chronic myelomonocytic leukaemia, and FIP1-like-1-PDGFRalpha, which causes hypereosinophilic syndrome, suggests potential use of AMN107 for myeloproliferative diseases characterised by these kinase fusions (Stover et al, 2005;Weisberg et al, 2005). AMN107 also inhibits the c-Kit receptor kinase, including the D816V-mutated variant of KIT, at pharmacologically achievable concentrations, supporting potential utility in the treatment of mastocytosis, and gastrointestinal stromal tumours von Bubnoff et al, 2005;Gleixner et al, 2006).…”

Section: Amn107 (Nilotinib)mentioning

confidence: 99%

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

et al. 2006

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Chronic myelogenous leukaemia (CML) and Philadelphia chromosome positive (Ph þ ) 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 þ 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 (IC50o30 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 þ 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 imatinibrefractory and late-stage disease are discussed.

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Section: Amn107 (Nilotinib)mentioning

confidence: 99%

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

et al. 2006

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“…The secondary mutations associated with t(8;21)-positive AML have therapeutic implications, as leukemias carrying the c-Kit N822K mutation may respond to tyrosine kinase inhibitors such as Imatinib [6]. In contrast, those leukemias bearing c-Kit D816 mutations are resistant to Imatinib [6], but may respond to the SRC/ABL inhibitor Dasatinib (BMS-354825) or to the tyrosine kinase inhibitor Nilotinib (AMN 107) [8,9].…”

Section: Introductionmentioning

confidence: 99%

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Elagib¹,

Goldfarb²

2007

Cancer Letters

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The leukemic fusion protein AML1-ETO occurs frequently in human acute myeloid leukemia (AML) and has received much attention over the past decade. An initial model for its pathogenetic effects emphasized the conversion of a hematopoietic transcriptional activator, RUNX1 (or AML1), into a leukemogenic repressor which blocked myeloid differentiation at the level of target gene regulation. This view has been absorbed into a larger picture of AML1-ETO pathogenesis, encompassing dysregulation of hematopoietic stem cell homeostasis at several mechanistic levels. Recent reports have highlighted a multifaceted capacity of AML1-ETO directly to inhibit key hematopoietic transcription factors that function as tumor suppressors at several nodal points during hematopoietic differentiation. A new model is presented in which AML1-ETO coordinates expansion of the stem cell compartment with diminished lineage commitment and with genome instability.

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“…[28][29][30] It has also been described that the novel TK inhibitor AMN107 (nilotinib) 31 down-regulates the growth of neoplastic cells exhibiting KIT-D816V at relatively high concentrations. 30,32 However, these compounds may not produce long-lasting complete remission in ASM or MCL. 29 Therefore, it is of importance to search further for novel KIT-targeting TK inhibitors and to examine co-operative drug effects.…”

Section: -5mentioning

confidence: 99%

Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT

Gleixner¹,

Mayerhofer²,

Sonneck³

et al. 2007

Haematologica

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The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107

Abstract: The systemic mastocytosis-specific activating cKit mutation D816V can be inhibited by the tyrosine kinase inhibitor AMN107

Cited by 63 publications

References 8 publications

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

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

Oncogenic pathways of AML1-ETO in acute myeloid leukemia: Multifaceted manipulation of marrow maturation

Synergistic growth-inhibitory effects of two tyrosine kinase inhibitors, dasatinib and PKC412, on neoplastic mast cells expressing the D816V-mutated oncogenic variant of KIT

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