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  • 1
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    Online Resource
    Bcr-Abl Resistance Screening Predicts a Limited Spectrum of Point Mutations To Be Associated with Clinical Resistance to the Abl Kinase Inhibitor AMN107.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 1983-1983
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 1983-1983
    Abstract: In advanced-phase CML, resistance to imatinib mesylate is frequently associated with point mutations in the Bcr-Abl kinase domain. New, highly potent Abl kinase inhibitors such as AMN107 and BMS-354824, have recently entered clinical trials. Data from analyses of resistant patients will be available not before a large number of resistant patients will have been treated within clinical trials. Therefore, it will be important to generate specific resistance profiles for each compound prior to its therapeutic application. Using a cell-based screening method for resistance of Bcr-Abl positive leukemia to Abl kinase inhibitors, we generated a resistance profile for AMN107 and compared it to the resistance profile of imatinib mesylate. In contrast to imatinib, resistance to AMN107 was associated with a very limited spectrum of Bcr-Abl kinase mutations. While 26 exchanges at 21 positions occured with imatinib, the AMN107 screen revealed eight different exchanges at seven amino acid positions, with four exchanges affecting the P-loop. Novel mutations which have never been observed with imatinib, either in vitro or in resistant patients, emerged in the presence of AMN107 including an F359 exchange to isoleucine and a Q252H/S349L double mutant. In contrast to imatinib, the frequency of resistant colonies dramatically decreased with increasing AMN107 concentrations. Rarely emerging resistant colonies at a concentration of 400 nM AMN107 exclusively contained T315I. With the exception of T315I, all mutations that were identified were effectively suppressed when AMN107 was increased to 2000 nM, a concentration which is achieved in plasma in treated patients. Thus, in this system, increasing the AMN107 concentration to 400 nM prevented the emergence of resistant colonies, with the exception of T315I. Our findings suggest that AMN107 might be superior to imatinib in terms of the development of resistance. Also, AMN107 at clinically relevant concentrations may overcome imatinib resistant disease, including cases with expression of P-loop mutations. However, our study indicates that clinical resistance to AMN107 may be associated with the predominant emergence of T315I. Using this or similar approaches, it will be possible to provide information that translates into combinatorial and sequential treatment strategies and to determine critical plasma concentrations for mutations that might occur during treatment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.1983.1983
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
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  • 2
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    Clinical and Preclinical Characterisation Of The Metabolites Of The BCR-ABL Tyrosine Kinase Inhibitor Nilotinib
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 4011-4011
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 4011-4011
    Abstract: There is a growing tendency for drugs to be grouped according to their perceived ‘class effects’, regardless of the different pharmacological profiles of the parent drugs and of their metabolites. Imatinib, dasatinib, nilotinib, bosutinib and, most recently ponatinib, are approved tyrosine kinase inhibitor (TKI) therapies for chronic myeloid leukemia (CML), which are clinically efficacious as a result of ABL1/ BCR-ABL inhibition. Following their oral administration at standard therapeutic doses, the parent drugs are the major circulating species by area under the curve (AUC). However in the case of imatinib, dasatinib, bosutinib and ponatinib, the exposure of patients to major metabolites can be substantial compared to that of parent drug, with CGP74588 (which is much less active than imatinib against both BCR-ABL and KIT; Bioorg Med Chem 2013;21:3231) representing 10% of imatinib by AUC (Clin Pharmacokinet 2005;44:879); M20 and M24 representing 45 and 25% of dasatinib (Drug Met Disp 2008;36:1341), M2 and M5 representing 19 and 25% of bosutinib (Clinical Pharmacology Biopharmaceutics Review, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm) and AP24600 representing 58% of ponatinib (Clinical Pharmacology Biopharmaceutics Review, http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm). Such major metabolites might make significant contributions to the on- and off-target effects of the parent drugs in vivoand may be responsible for some of the side-effects observed in patients. Here we report on the metabolism of the potent and selective BCR-ABL inhibitor, nilotinib and the preclinical profile of its major metabolites. Methods The metabolism of nilotinib was characterised in healthy subjects after oral administration of two capsules containing 200 mg [14C] -labelled nilotinib (50 μCi), and blood plasma, feces and urine samples were assayed in an appropriate scintillant either by counting an aliquot directly or after homogenisation, air-drying and solubilisation. Metabolites were characterised and quantified by HPLC with radioactivity detection and identified by mass spectrometry (LC-MS/MS) and, when possible, co-elution with non-radiolabeled authentic samples. Synthesised samples of the metabolites were evaluated in a large panel of assays for potential effects on kinase and non-kinase enzymes, G-protein coupled receptors, cell transporters, ion channels and nuclear receptors. Results The oral absorption of nilotinib was determined to be ≥30% and excretion was mainly into the feces (93.5% of administered radioactivity), with neither nilotinib nor the identified metabolites being detected in the urine. Unchanged nilotinib was the major circulating component in human plasma, accounting for 87.5±9.2% of the total drug-related AUC. The main circulating metabolites were P41.6 (4.7% AUC), P36.5 (6.1% AUC), formed from oxidation of the methyl group in the methyl-imidazole moiety to a hydroxyl or carboxylic acid group, and P42.1 (1.3% AUC) resulting from oxidation of the phenyl-methyl group. Other, more minor metabolites included the pyridine N-oxide P36 and P50, resulting from degradation of the imidazole. All of the metabolites identified in humans were also observed in one or more of the animal species, employed for preclinical safety studies, with the exception of the minor fecal metabolites P38 (pyridine- + pyrimidine-N-oxide) and P40 (pyridine-N-oxide). In comparison to the parent nilotinib, which inhibits the BCR-ABL and KIT tyrosine kinases with mean cellular IC50 values of 20 and 217 nM, only P41.6 (19 and 284 nM), P42.1 (256 and 714 nM) and P50 (39 and 67 nM) exhibited kinase inhibition at concentrations 〈 2200 nM. In addition, none of the metabolites showed substantial activity at concentrations 〈 3000 nM against non-kinase targets. Conclusion Following oral administration of nilotinib to humans the predominant circulating species was the parent drug, with 〉 15 minor and trace metabolites being identified. Given their in vitro potencies and target profiles, none of the metabolites are expected to contribute to the in vivo pharmacology of the parent nilotinib. This data further distinguishes the profile of nilotinib from other TKIs used for the treatment of CML. Disclosures: Manley: Novartis Pharmaceuticals: Employment. Sheng:Novartis Pharmaceuticals: Employment. Tran:Novartis Pharmaceuticals: Employment. Kagan:Novartis Pharmaceuticals: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.4011.4011
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 3
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    Abstract 2664: PQR309: Structure-based design, synthesis and biological evaluation of a novel, selective, dual pan-PI3K/mTOR inhibitor
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2664-2664
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2664-2664
    Abstract: Phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling is key to the control of many physiological and pathophysiological processes, and promotes cancer and inflammatory disease. Therefore, targeting of PI3K and/or mTOR pathways is currently explored in numerous clinical studies. PQR309 is a novel, brain penetrant, potent and selective pan-PI3K/mTOR inhibitor with PK properties suitable for once a day oral dosing in humans. Structure activity relationship studies for PI3K and mTOR interactions are presented, including X-Ray analysis of PI3Kgamma co-crystal structures, modeling of PI3Kalpha and mTOR structures, and chemical derivatization. This led to the identification of PQR309 as a potent pan-PI3K and moderate mTOR inhibitor. PQR309 displays excellent selectivity versus PI3K-related lipid kinases (PIKKs) and protein kinases (KINOMEscan), as well as excellent selectivity versus unrelated targets (Cerep expresSProfile). PQR309 features excellent cell permeability, and was characterized as a BCS class II compound due to its limited water solubility (40 μM). Moreover, PQR309 is not a substrate for P-glycoprotein 1 (P-gp). In A2058 melanoma cells PQR309 demonstrated inhibition of protein kinase B (PKB/Akt; pS473) and ribosomal protein S6 (S6, pSer235/236) phosphorylation with IC50 values of 0.13 μM and 0.58 μM, respectively. In IGF-stimulated MCF7 breast cancer cells, PQR309 at 1 μM inhibited phosphorylation of downstream substrates of PI3K including PKB/Akt, S6, p70S6 kinase, GSK3 and Bad by 60-95%. PQR309 inhibited proliferation of all 58 cell lines of the NCI60 panel (GI50 from 50 to 3300 nM), of the NTRC Oncoline panel (44 cell lines, GI50 from 100-6700 nM) and of a lymphoma cell line panel (40 lymphoma cell lines, GI50 from 25-1740 nM). A concise 4-step synthetic process utilizing a novel protective group strategy provides a robust and scalable supply of PQR309 for clinical trials. In summary, PQR309 is a novel, potent, dual pan-PI3K/mTOR inhibitor with a balanced PI3K vs. mTOR profile, and displays excellent physico-chemical and pharmacological properties. The safety profile of PQR309 is currently addressed in Phase I clinical studies. Citation Format: Vladimir Cmiljanovic, Natasa Cmiljanovic, Romina Marone, Florent Beaufils, Xuxiao Zhang, Marketa Zvelebil, Paul Hebeisen, Marc Lang, Juergen Mestan, Anna Melone, Thomas Bohnacker, Eugenio Gaudio, Chiara Tarantelli, Francesco Bertoni, Reto Ritschard, Vincent Pretre, Andreas Wicki, Doriano Fabbro, Petra Hillmann, Roger Williams, Bernd Giese, Matthias P. Wymann. PQR309: Structure-based design, synthesis and biological evaluation of a novel, selective, dual pan-PI3K/mTOR inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2664. doi:10.1158/1538-7445.AM2015-2664
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-2664
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
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    Abstract 4514: PQR309: A potent, brain-penetrant, dual pan-PI3K/mTOR inhibitor with excellent oral bioavailability and tolerability
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4514-4514
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4514-4514
    Abstract: The phosphatidylinositol 3-kinase (PI3K) signaling pathway is frequently activated in tumors and promotes oncogenic cell transformation, proliferation and tumor growth. PQR309, a novel dual inhibitor of PI3K and mTOR, is currently in Phase I clinical development in cancer patients. PQR309 binds potently and specifically to the ATP binding pocket of all PI3K class I isoforms and mTORC1/2, attenuates PI3K signaling and inhibits tumor cell growth. The preclinical pharmacological and toxicological characterization of PQR309 is presented here. Methods: PQR309 pharmacokinetics/-dynamics (PK/PD) were investigated in rats and mice. Tissue samples from plasma, brain and liver were analyzed by LC/MS detecting PQR309 distribution as well as blood insulin and glucose. Toxicological studies were performed in rats and dogs. Effects on neurological, hematopoietic, respiratory, lymphoid, reproductive and cardiovascular system as well as general health were monitored. The metabolic fate of PQR309 was analyzed in rat, dog and human hepatocytes. Results: PQR309 PK studies in rats, mice and dogs revealed dose-proportional PK, both PO and IV, with a half-life of 5-8 hours in plasma, brain and liver, allowing for once a day oral application. As on-target effect, increase of blood insulin and glucose could be observed within hours after oral dosage in rats, which makes both molecules suitable as PD markers. In in vivo PC-3 rat tumor xenograft models, PQR309 effectively inhibited PI3K signaling in tumors and reduced tumor growth at 10 mg/kg oral dosing. Preclinical toxicity testing showed no signs of cardiotoxicity (including lack of hERG binding), phototoxicity (3T3 NRU test) or mutagenicity (AMES test) for PQR309. No marked effect on CYP450 activity was observed making PQR309 a good combination partner in cancer therapy. As for other PI3K inhibitors, PQR309 leads at elevated doses to a fully reversible loss of body weight and appetite in rats and dogs. No further significant adverse events were observed when testing PQR309 for 28 days in these species. Conclusions: PQR309 potently inhibits class I PI3K isoforms and mTORC1/2 and shows anti-tumor effects in vitro and in vivo. The physico-chemical properties of PQR309 result in good oral bioavailability and equal distribution between plasma and brain. Pre-clinical data led to initiation of a Phase I clinical study of PQR309 in solid tumors. Citation Format: Vladimir Cmiljanovic, Robert A. Ettlin, Florent Beaufils, Walter Dieterle, Petra Hillmann, Juergen Mestan, Anna Melone, Thomas Bohnacker, Marc Lang, Natasa Cmiljanovic, Bernd Giese, Paul Hebeisen, Matthias P. Wymann, Doriano Fabbro. PQR309: A potent, brain-penetrant, dual pan-PI3K/mTOR inhibitor with excellent oral bioavailability and tolerability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4514. doi:10.1158/1538-7445.AM2015-4514
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4514
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis
    Elsevier BV ; 2004
    In:  Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics Vol. 1697, No. 1-2 ( 2004-03), p. 17-27
    Details
    In: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Elsevier BV, Vol. 1697, No. 1-2 ( 2004-03), p. 17-27
    Type of Medium: Online Resource
    ISSN: 1570-9639
    URL: Article
    DOI: 10.1016/j.bbapap.2003.11.010
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
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    SSG: 12
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  • 6
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    Extended kinase profile and properties of the protein kinase inhibitor nilotinib
    Elsevier BV ; 2010
    In:  Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics Vol. 1804, No. 3 ( 2010-03), p. 445-453
    Details
    In: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Elsevier BV, Vol. 1804, No. 3 ( 2010-03), p. 445-453
    Type of Medium: Online Resource
    ISSN: 1570-9639
    URL: Article
    DOI: 10.1016/j.bbapap.2009.11.008
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2010
    detail.hit.zdb_id: 2209540-8
    SSG: 12
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  • 7
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    Allosteric inhibitors of Bcr-abl–dependent cell proliferation
    Springer Science and Business Media LLC ; 2006
    In:  Nature Chemical Biology Vol. 2, No. 2 ( 2006-2), p. 95-102
    Details
    In: Nature Chemical Biology, Springer Science and Business Media LLC, Vol. 2, No. 2 ( 2006-2), p. 95-102
    Type of Medium: Online Resource
    ISSN: 1552-4450 , 1552-4469
    URL: Article
    DOI: 10.1038/nchembio760
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2006
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  • 8
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    Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases
    Elsevier BV ; 2004
    In:  Bioorganic & Medicinal Chemistry Letters Vol. 14, No. 23 ( 2004-12), p. 5793-5797
    Details
    In: Bioorganic & Medicinal Chemistry Letters, Elsevier BV, Vol. 14, No. 23 ( 2004-12), p. 5793-5797
    Type of Medium: Online Resource
    ISSN: 0960-894X
    URL: Article
    DOI: 10.1016/j.bmcl.2004.09.042
    RVK:
    VA 2620
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
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  • 9
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    IL-8-mediated angiogenic responses of endothelial cells to lipid antigen activation of iNKT cells depend on EGFR transactivation
    Oxford University Press (OUP) ; 2011
    In:  Journal of Leukocyte Biology Vol. 90, No. 5 ( 2011-08-01), p. 929-939
    Details
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 90, No. 5 ( 2011-08-01), p. 929-939
    Abstract: iNKT cells are a unique T cell subset, which is CD1d-restricted and specific for glycolipid antigens. In advanced atherosclerotic plaques, focal collections of inflammatory cells correlate with areas of intraplaque neovascularization. We reported recently that iNKT cells might facilitate intraplaque neovascularization by enhancing EC migration and sprouting in an IL-8-dependent manner. This study investigated the participating effector mechanisms. In ECs, CM, derived from antigen-stimulated human iNKT cells (CM+), induced up-regulation of IL-8R CXCR2 and the phosphorylation of EGFR and of multiple intracellular signaling effectors, including FAK, Src, Erk, Jnk, p38-MAPK, and STAT1 and -3. We found that a cascade of events, which were IL-8-dependent and involved EGFR activation, was responsible for signaling through FAK and Src kinases and necessary for acquisition of angiogenic morphology, migration in a two-dimensional wound assay, and sprout outgrowth in a three-dimensional model of angiogenesis in vitro. The data support that IL-8-dependent activation of angiogenic behavior in ECs, in response to activated iNKT, involves CXCR2, transactivation of EGFR, and subsequent FAK/Src signaling. We found too that activated iNKT increased VEGFR2 expression in ECs. Functional studies confirmed that EGF is the motogenic-enhancing factor in CM+ and is necessary, together with an exogenous source of VEGF, for iNKT-promoted sprout formation. EGFR inhibition may represent a novel therapeutic modality aimed at plaque stabilization through control of neovascularization within developing atherosclerotic plaques.
    Type of Medium: Online Resource
    ISSN: 0741-5400 , 1938-3673
    URL: Article
    DOI: 10.1189/jlb.0211097
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2011
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  • 10
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    In vivo antitumor activity of NVP-AEW541—A novel, potent, and selective inhibitor of the IGF-IR kinase
    Elsevier BV ; 2004
    In:  Cancer Cell Vol. 5, No. 3 ( 2004-03), p. 231-239
    Details
    In: Cancer Cell, Elsevier BV, Vol. 5, No. 3 ( 2004-03), p. 231-239
    Type of Medium: Online Resource
    ISSN: 1535-6108
    URL: Article
    DOI: 10.1016/S1535-6108(04)00051-0
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
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    SSG: 12
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