Keith B Glaser

Summary

Affiliation: Abbott Laboratories
Country: USA

Publications

  1. ncbi request reprint Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor
    Daniel H Albert
    Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47J, Building AP9 2, 100 Abbott Park Road, Abbott Park, IL 60064 3500, USA
    Mol Cancer Ther 5:995-1006. 2006
  2. ncbi request reprint HDAC inhibitors: clinical update and mechanism-based potential
    Keith B Glaser
    Department of Cancer Research, R47J AP9, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Pharmacol 74:659-71. 2007
  3. pmc ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia
    Deepa B Shankar
    Division of Hematology Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
    Blood 109:3400-8. 2007
  4. doi request reprint A renaissance in marine pharmacology: from preclinical curiosity to clinical reality
    Keith B Glaser
    Cancer Research R47J AP9, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Pharmacol 78:440-8. 2009
  5. ncbi request reprint Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase
    Keith B Glaser
    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064 6121, USA
    Mol Cancer Ther 1:759-68. 2002
  6. ncbi request reprint Role of class I and class II histone deacetylases in carcinoma cells using siRNA
    Keith B Glaser
    Cancer Research, R47J AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Biophys Res Commun 310:529-36. 2003
  7. ncbi request reprint Differential protein acetylation induced by novel histone deacetylase inhibitors
    K B Glaser
    Cancer Research R47J AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Biophys Res Commun 325:683-90. 2004
  8. doi request reprint 3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases
    Zhiqin Ji
    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064 6100, USA
    J Med Chem 51:1231-41. 2008
  9. ncbi request reprint Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor
    Yujia Dai
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064 6100, USA
    J Med Chem 50:1584-97. 2007
  10. ncbi request reprint Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors
    Jun Guo
    Cancer Discovery Research R47J, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Mol Cancer Ther 5:1007-13. 2006

Collaborators

Detail Information

Publications42

  1. ncbi request reprint Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor
    Daniel H Albert
    Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R47J, Building AP9 2, 100 Abbott Park Road, Abbott Park, IL 60064 3500, USA
    Mol Cancer Ther 5:995-1006. 2006
    ..08 microg/mL, >or=7 hours) than with plasma area under the curve or Cmax. These results support clinical assessment of ABT-869 as a therapeutic agent for cancer...
  2. ncbi request reprint HDAC inhibitors: clinical update and mechanism-based potential
    Keith B Glaser
    Department of Cancer Research, R47J AP9, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Pharmacol 74:659-71. 2007
    ..The question that must be considered is whether the current HDACIs are being utilized to their fullest potential in clinical trials based on their mechanism-based alterations in disease processes...
  3. pmc ABT-869, a multitargeted receptor tyrosine kinase inhibitor: inhibition of FLT3 phosphorylation and signaling in acute myeloid leukemia
    Deepa B Shankar
    Division of Hematology Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
    Blood 109:3400-8. 2007
    ..In tumors, ABT-869 inhibited FLT3 phosphorylation, induced apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL]) and decreased proliferation (Ki67). ABT-869 is under clinical development for AML...
  4. doi request reprint A renaissance in marine pharmacology: from preclinical curiosity to clinical reality
    Keith B Glaser
    Cancer Research R47J AP9, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Pharmacol 78:440-8. 2009
    ....
  5. ncbi request reprint Transforming growth factor beta mimetics: discovery of 7-[4-(4-cyanophenyl)phenoxy]-heptanohydroxamic acid, a biaryl hydroxamate inhibitor of histone deacetylase
    Keith B Glaser
    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064 6121, USA
    Mol Cancer Ther 1:759-68. 2002
    ..These results and those of others demonstrate the importance of HDACs in regulation of the TGF-beta signaling pathway(s)...
  6. ncbi request reprint Role of class I and class II histone deacetylases in carcinoma cells using siRNA
    Keith B Glaser
    Cancer Research, R47J AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Biophys Res Commun 310:529-36. 2003
    ..These results and the positive preclinical results with non-specific inhibitors of the HDAC enzymes provide further support for the development of Class I selective HDAC inhibitors as cancer therapeutics...
  7. ncbi request reprint Differential protein acetylation induced by novel histone deacetylase inhibitors
    K B Glaser
    Cancer Research R47J AP9, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Biochem Biophys Res Commun 325:683-90. 2004
    ..These data suggest "selectivity" can be observed at the cellular level with HDAC inhibitors and that the nature of the zinc-chelating moiety is an important determinant of activity against tubulin deacetylase...
  8. doi request reprint 3-amino-benzo[d]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases
    Zhiqin Ji
    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064 6100, USA
    J Med Chem 51:1231-41. 2008
    ..In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day...
  9. ncbi request reprint Discovery of N-(4-(3-amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor
    Yujia Dai
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064 6100, USA
    J Med Chem 50:1584-97. 2007
    ..In particular, compound 17p (ABT-869) was found to possess favorable pharmacokinetic profiles across different species and display significant tumor growth inhibition in multiple preclinical animal models...
  10. ncbi request reprint Inhibition of phosphorylation of the colony-stimulating factor-1 receptor (c-Fms) tyrosine kinase in transfected cells by ABT-869 and other tyrosine kinase inhibitors
    Jun Guo
    Cancer Discovery Research R47J, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Mol Cancer Ther 5:1007-13. 2006
    ..These results show the use of a cell-based assay to confirm the inhibitory activity of lead compounds and drug candidates, such as ABT-869, against the CSF-1R protein in situ...
  11. ncbi request reprint Trifluoromethyl ketones as inhibitors of histone deacetylase
    Robin R Frey
    Cancer Research, Abbott Laboratories, Abbott Park, IL 60064, USA
    Bioorg Med Chem Lett 12:3443-7. 2002
    ..Optimization of this series led to the identification of submicromolar inhibitors such as 20 that demonstrated antiproliferative effects against the HT1080 and MDA 435 cell lines...
  12. doi request reprint 7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors
    Robin R Frey
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064 6100, USA
    J Med Chem 51:3777-87. 2008
    ..In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg)...
  13. ncbi request reprint A novel series of histone deacetylase inhibitors incorporating hetero aromatic ring systems as connection units
    Yujia Dai
    Cancer Research, Abbott Laboratories, Department R47J, Building AP10, 100 Abbott Park Road, Abbott Park, IL 60031, USA
    Bioorg Med Chem Lett 13:3817-20. 2003
    ..These new inhibitors are very potent in in vitro enzymatic assays and display antiproliferation activity against two human cancer cell lines...
  14. ncbi request reprint Identification of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors
    Yujia Dai
    Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 18:386-90. 2008
    ..Here, we report a series of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors. A number of compounds have been identified to be orally bioavailable and efficacious in the mouse edema model...
  15. ncbi request reprint Isothiazolopyrimidines and isoxazolopyrimidines as novel multi-targeted inhibitors of receptor tyrosine kinases
    Zhiqin Ji
    Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 16:4326-30. 2006
    ..The selected compounds 8 and 13 display 56% and 48% oral bioavailability in mice, respectively...
  16. doi request reprint Preclinical characterization of ABT-348, a kinase inhibitor targeting the aurora, vascular endothelial growth factor receptor/platelet-derived growth factor receptor, and Src kinase families
    Keith B Glaser
    Abbott Oncology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA
    J Pharmacol Exp Ther 343:617-27. 2012
    ..These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer...
  17. doi request reprint Pyrazole diaminopyrimidines as dual inhibitors of KDR and Aurora B kinases
    Michael L Curtin
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 22:4750-5. 2012
    ..Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents...
  18. ncbi request reprint Thienopyridine urea inhibitors of KDR kinase
    H Robin Heyman
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 17:1246-9. 2007
    ..Further characterization of inhibitor 2 indicated that this analog possessed excellent in vivo potency (ED50 2.1 mg/kg) as measured in an estradiol-induced mouse uterine edema model...
  19. ncbi request reprint Indole amide hydroxamic acids as potent inhibitors of histone deacetylases
    Yujia Dai
    Cancer Research, Abbott Laboratories, Dept R47J, Bldg AP10, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 13:1897-901. 2003
    ..A representative compound in the series, 7b, has been found to be orally active in tumor growth inhibition model...
  20. doi request reprint Thienopyridine ureas as dual inhibitors of the VEGF and Aurora kinase families
    Michael L Curtin
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 22:3208-12. 2012
    ..Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations...
  21. ncbi request reprint Thienopyrimidine ureas as novel and potent multitargeted receptor tyrosine kinase inhibitors
    Yujia Dai
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064 6100, USA
    J Med Chem 48:6066-83. 2005
    ..day, per os (po))...
  22. doi request reprint Discovery of potent and selective thienopyrimidine inhibitors of Aurora kinases
    William J McClellan
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 21:5620-4. 2011
    ..Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors...
  23. ncbi request reprint Expression and functional characterization of recombinant human HDAC1 and HDAC3
    Junling Li
    Global Pharmaceutical Research and Development, Cancer Research, R47J AP9, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Life Sci 74:2693-705. 2004
    ....
  24. ncbi request reprint Alpha-keto amides as inhibitors of histone deacetylase
    Carol K Wada
    Cancer Research, Abbott Laboratories, Department R47J, Bldg AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Bioorg Med Chem Lett 13:3331-5. 2003
    ..Nanomolar inhibitors against the isolated enzyme and sub-micromolar inhibitors of cellular proliferation were obtained. The alpha-keto amide 30 also exhibited significant anti-tumor effects in an in vivo tumor model...
  25. ncbi request reprint Heterocyclic ketones as inhibitors of histone deacetylase
    Anil Vasudevan
    Medicinal Chemistry Technologies, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Bioorg Med Chem Lett 13:3909-13. 2003
    ..Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition...
  26. doi request reprint Exploration of diverse hinge-binding scaffolds for selective Aurora kinase inhibitors
    Zhiqin Ji
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 22:4528-31. 2012
    ..Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated...
  27. pmc ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet-derived growth factor receptor beta and c-KIT signaling pathways
    Alan K Ikeda
    Division of Hematology Oncology, Department of Pediatrics, Gwynne Hazen Cherry Memorial Laboratories, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, California 90095 1752, USA
    Mol Cancer Ther 9:653-60. 2010
    ..Therefore, our in vitro and in vivo studies show that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRbeta and c-KIT pathways...
  28. ncbi request reprint Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines
    Keith B Glaser
    Cancer Research and Advanced Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064 6121, USA
    Mol Cancer Ther 2:151-63. 2003
    ..These data will aide in understanding the complex set of events in cells in response to chromatin remodeling induced by HDAC inhibition, which may be responsible for antitumor effects...
  29. pmc 1-Benzyl-3-cetyl-2-methylimidazolium iodide (NH125) induces phosphorylation of eukaryotic elongation factor-2 (eEF2): a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor
    Zehan Chen
    Cancer Research and Advanced Technology, Abbott Laboratories, Abbott Park, Illinois 60064 6099, USA
    J Biol Chem 286:43951-8. 2011
    ..Preliminary data suggested that NH125-induced eEF2 phosphorylation was likely mediated through multiple pathways. These observations identified an opportunity for a new multipathway approach to anticancer therapies...
  30. ncbi request reprint Succinimide hydroxamic acids as potent inhibitors of histone deacetylase (HDAC)
    Michael L Curtin
    Cancer Research Area, Abbott Laboratories, Dept 47J, Bldg AP10, 100 Abbott Park Road, Abbott Park, IL 60064, USA
    Bioorg Med Chem Lett 12:2919-23. 2002
    ..While the original macrocyclic analogue 6 was quite potent in both assays, several appropriately substituted non-macrocyclic succinimides, such as 23, were equipotent...
  31. doi request reprint Scaffold oriented synthesis. Part 2: Design, synthesis and biological evaluation of pyrimido-diazepines as receptor tyrosine kinase inhibitors
    Vijaya Gracias
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60044, USA
    Bioorg Med Chem Lett 18:2691-5. 2008
    ..Compound 14 exhibited low nanomolar KDR enzymatic and cellular potencies (IC(50)=9 and 52 nM, respectively)...
  32. pmc The multitargeted receptor tyrosine kinase inhibitor linifanib (ABT-869) induces apoptosis through an Akt and glycogen synthase kinase 3β-dependent pathway
    Jenny E Hernandez-Davies
    Division of Hematology Oncology, Gwynne Hazen Cherry Memorial Laboratories, Mattel Children s Hospital UCLA, Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA 90095, USA
    Mol Cancer Ther 10:949-59. 2011
    ..In addition, we show that inhibition of GSK3β decreases linifanib-induced apoptosis. This study shows the importance of GSK3 as a potential target for AML therapy, particularly in patients with FLT3 ITD mutations...
  33. ncbi request reprint Fluorescence assay of SIRT protein deacetylases using an acetylated peptide substrate and a secondary trypsin reaction
    Patrick A Marcotte
    Cancer Discovery Research Group, Abbott Laboratories Global Pharmaceutical Research and Development, Abbott Park, IL 60064, USA
    Anal Biochem 332:90-9. 2004
    ..Several nicotinamide analogs have also been tested as inhibitors and found to have much lower affinity for these enzymes than does the parent compound...
  34. ncbi request reprint Isoindolinone ureas: a novel class of KDR kinase inhibitors
    Michael L Curtin
    Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064 6100, USA
    Bioorg Med Chem Lett 14:4505-9. 2004
    ..A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site...
  35. ncbi request reprint Enhancement of the surface expression of tumor necrosis factor alpha (TNFalpha) but not the p55 TNFalpha receptor in the THP-1 monocytic cell line by matrix metalloprotease inhibitors
    K B Glaser
    Cancer Research, Abbott Laboratories, Abbott Park, IL 60064 3500, USA
    Biochem Pharmacol 57:291-302. 1999
    ..The potential "deleterious" implications of high levels of surface pro-TNFalpha expression in the presence of these inhibitors may be lessened by its transient nature...
  36. pmc Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization
    O Jameel Shah
    Oncology Division and Advanced Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Proc Natl Acad Sci U S A 107:12634-9. 2010
    ..These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility...
  37. doi request reprint Identification of genes that confer tumor cell resistance to the aurora B kinase inhibitor, AZD1152
    J Guo
    Cancer Biology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Pharmacogenomics J 9:90-102. 2009
    ..The data provide a genetic basis for resistance to Aurora kinase inhibitors, which could be utilized to predict clinical response to therapy...
  38. doi request reprint Inhibition of Aurora B kinase sensitizes a subset of human glioma cells to TRAIL concomitant with induction of TRAIL-R2
    J Li
    Cancer Biology Division, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064 6121, USA
    Cell Death Differ 16:498-511. 2009
    ..Our data shed light on the apoptotic program induced during polyploidization and suggest that TRAIL-R2 activation is a putative point of therapeutic intervention in combination with inhibitors of Aurora B...
  39. ncbi request reprint Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo
    Steffen Zopf
    Department of Medicine 1, University Hospital Erlangen, D 91054, Erlangen, Germany
    Int J Oncol 31:1391-402. 2007
    ..0 on the extrinsic cell death pathway through activation of TRAIL and its signalling pathway indicate that A-423378.0 may be a potent new therapeutic compound for the treatment of advanced colorectal cancer...
  40. ncbi request reprint In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor
    Jianbiao Zhou
    Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    Leuk Res 32:1091-100. 2008
    ..ABT-869 also reduced the leukemia burden and prolonged survival. Our study supports the rationale for clinically testing an anti-angiogenesis agent in AML with wild-type FLT3...
  41. ncbi request reprint Defining the role of gene regulation in resistance to HDAC inhibitors--mechanisms beyond P-glycoprotein
    Keith B Glaser
    Leuk Res 30:651-2. 2006
    ....
  42. pmc G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells
    Venugopalan Cheriyath
    Center for Hematology and Oncology Molecular Therapeutics, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA
    J Clin Invest 117:3107-17. 2007
    ..Our data identify the direct role of a mitochondria-localized prosurvival ISG in antagonizing the effect of TRAIL. Curtailing G1P3-mediated antiapoptotic signals could improve therapies for myeloma or other malignancies...