pyrimidines

Summary

Summary: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.

Top Publications

  1. ncbi Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein
    Paul M Ridker
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    N Engl J Med 359:2195-207. 2008
  2. pmc Role of AMP-activated protein kinase in mechanism of metformin action
    G Zhou
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Clin Invest 108:1167-74. 2001
  3. ncbi Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial
    Cora N Sternberg
    FACP, Department of Medical Oncology, San Camillo Forlanini Hospital, Circonvallazione Gianicolense 87, Rome, Italy 00152
    J Clin Oncol 28:1061-8. 2010
  4. ncbi Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia
    Brian J Druker
    Oregon Health and Science University Cancer Institute, L592, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
    N Engl J Med 355:2408-17. 2006
  5. ncbi An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
    Teresa A Soucy
    Discovery, Millennium Pharmaceuticals, Inc, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA
    Nature 458:732-6. 2009
  6. ncbi Diagnosis of gastrointestinal stromal tumors: A consensus approach
    Christopher D M Fletcher
    Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Boston MA 02115, USA
    Hum Pathol 33:459-65. 2002
  7. ncbi Receptors for purines and pyrimidines
    V Ralevic
    School of Biomedical Sciences, Queen s Medical Centre, University of Nottingham, Nottingham, England
    Pharmacol Rev 50:413-92. 1998
  8. ncbi Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia
    Hagop Kantarjian
    Department of Leukemia, University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    N Engl J Med 362:2260-70. 2010
  9. ncbi One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial
    Heikki Joensuu
    Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN 00029 Helsinki, Finland
    JAMA 307:1265-72. 2012
  10. pmc Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism
    Paul B Yu
    Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Nat Chem Biol 4:33-41. 2008

Detail Information

Publications365 found, 100 shown here

  1. ncbi Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein
    Paul M Ridker
    Center for Cardiovascular Disease Prevention, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02215, USA
    N Engl J Med 359:2195-207. 2008
    ....
  2. pmc Role of AMP-activated protein kinase in mechanism of metformin action
    G Zhou
    Department of Molecular Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Clin Invest 108:1167-74. 2001
    ..Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders...
  3. ncbi Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial
    Cora N Sternberg
    FACP, Department of Medical Oncology, San Camillo Forlanini Hospital, Circonvallazione Gianicolense 87, Rome, Italy 00152
    J Clin Oncol 28:1061-8. 2010
    ..CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC...
  4. ncbi Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia
    Brian J Druker
    Oregon Health and Science University Cancer Institute, L592, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA
    N Engl J Med 355:2408-17. 2006
    ..Imatinib inhibits this kinase, and in a short-term study was superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. For 5 years, we followed patients with CML who received imatinib as initial therapy...
  5. ncbi An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer
    Teresa A Soucy
    Discovery, Millennium Pharmaceuticals, Inc, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA
    Nature 458:732-6. 2009
    ..MLN4924 suppressed the growth of human tumour xenografts in mice at compound exposures that were well tolerated. Our data suggest that NAE inhibitors may hold promise for the treatment of cancer...
  6. ncbi Diagnosis of gastrointestinal stromal tumors: A consensus approach
    Christopher D M Fletcher
    Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Boston MA 02115, USA
    Hum Pathol 33:459-65. 2002
    ....
  7. ncbi Receptors for purines and pyrimidines
    V Ralevic
    School of Biomedical Sciences, Queen s Medical Centre, University of Nottingham, Nottingham, England
    Pharmacol Rev 50:413-92. 1998
  8. ncbi Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia
    Hagop Kantarjian
    Department of Leukemia, University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    N Engl J Med 362:2260-70. 2010
    ..We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML...
  9. ncbi One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial
    Heikki Joensuu
    Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN 00029 Helsinki, Finland
    JAMA 307:1265-72. 2012
    ..Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo...
  10. pmc Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism
    Paul B Yu
    Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Nat Chem Biol 4:33-41. 2008
    ..These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis...
  11. pmc Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2
    Morris E Feldman
    Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, USA
    PLoS Biol 7:e38. 2009
    ..These potent new pharmacological agents complement rapamycin in the study of mTOR and its role in normal physiology and human disease...
  12. ncbi Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial
    Francois Xavier Mahon
    Laboratoire d Hématologie et Service des Maladies du Sang, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
    Lancet Oncol 11:1029-35. 2010
    ..We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib...
  13. ncbi Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia
    Giuseppe Saglio
    University of Turin, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
    N Engl J Med 362:2251-9. 2010
    ..We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase...
  14. ncbi Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis
    Raoul Herbrecht
    Département d Hématologie et d Oncologie, Hopital de Hautepierre, Strasbourg, France
    N Engl J Med 347:408-15. 2002
    ..Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis...
  15. ncbi Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
    George D Demetri
    Dana Farber Cancer Institute and Harvard Cancer Center, Boston, MA 02115, USA
    N Engl J Med 347:472-80. 2002
    ..Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors...
  16. ncbi Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia
    A Hochhaus
    Universitatsmedizin Mannheim, Heidelberg University, Mannheim, Germany
    Leukemia 23:1054-61. 2009
    ..The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML...
  17. ncbi Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial
    Steven E Nissen
    Department of Cardiovascular Medicine, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio 44195, USA
    JAMA 295:1556-65. 2006
    ....
  18. pmc Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial
    Ronald P Dematteo
    Memorial Sloan Kettering Cancer Center, New York, NY, USA
    Lancet 373:1097-104. 2009
    ..We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour...
  19. ncbi Somatic activation of KIT in distinct subtypes of melanoma
    John A Curtin
    Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143 0808, USA
    J Clin Oncol 24:4340-6. 2006
    ..This raises the question of whether other aberrations are occurring in the MAP kinase cascade in the melanoma types with infrequent mutations of BRAF and NRAS...
  20. ncbi Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial
    Winette T A van der Graaf
    Radboud University Medical Centre, Department of Medical Oncology, Nijmegen, Netherlands
    Lancet 379:1879-86. 2012
    ..We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy...
  21. ncbi Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
    Neil P Shah
    Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Cancer Cell 2:117-25. 2002
    ..Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance...
  22. ncbi Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL
    Hagop Kantarjian
    Department of Leukemia, University of Texas M D Anderson Cancer Center, Houston, TX 77230 1402, USA
    N Engl J Med 354:2542-51. 2006
    ..Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50...
  23. pmc The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors
    Michael Hedvat
    Molecular Medicine, Beckman Research Institute, Irell and Manella Graduate School of Biological Sciences, City of Hope Cancer Center, Duarte, CA 91010, USA
    Cancer Cell 16:487-97. 2009
    ..We demonstrate the essential role of Stat3 downstream of Jaks by inhibition of tumor growth using short hairpin RNA targeting Stat3. Our data support a key role of Jak kinase activity in Stat3-dependent tumorigenesis...
  24. ncbi Protein kinases--the major drug targets of the twenty-first century?
    Philip Cohen
    Medical Research Council, Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK
    Nat Rev Drug Discov 1:309-15. 2002
    ..Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field...
  25. ncbi Rosuvastatin in older patients with systolic heart failure
    John Kjekshus
    Department of Cardiology, University of Oslo, Rikshospitalet University Hospital, Oslo, Norway
    N Engl J Med 357:2248-61. 2007
    ..Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients...
  26. ncbi Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT
    Charles D Blanke
    Oregon Health and Science University Cancer Center and Portland Veterans Affairs Hospital, Portland, OR, USA
    J Clin Oncol 26:620-5. 2008
    ..We conducted a long-term analysis of patients treated on the trial, including patients followed during an extension phase, to evaluate survival, patterns of failure, and potential prognostic factors, including tumor mutational status...
  27. ncbi The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia
    Martin F M de Rooij
    Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
    Blood 119:2590-4. 2012
    ....
  28. ncbi Assessment of BCR-ABL1 transcript levels at 3 months is the only requirement for predicting outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors
    David Marin
    Department of Haematology, Imperial College London, Hammersmith Hospital, Du Cane Rd, London W12 0NN, United Kingdom
    J Clin Oncol 30:232-8. 2012
    ....
  29. ncbi Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification
    M E Gorre
    Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA
    Science 293:876-80. 2001
    ..These studies provide evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggest a strategy for identifying inhibitors of STI-571 resistance...
  30. pmc Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2
    Xianming Deng
    Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
    Nat Chem Biol 7:203-5. 2011
    ..LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease...
  31. ncbi Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs
    Roy Fleischmann
    Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX 75231, USA
    Arthritis Rheum 64:617-29. 2012
    ....
  32. ncbi Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO
    J Y Blay
    Unité Inserm 590, Centre Leon Berard, 69008 Lyon and Hopital Edouard Herriot, Place d Arsonval, 69003 Lyon, France
    Ann Oncol 16:566-78. 2005
    ..The objectives of this international consensus meeting were to describe the optimal management procedures for patients with GIST in localized and advanced stages, as well as research issues for the future...
  33. ncbi Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 620
    Stefan Sleijfer
    Dept of Medical Oncology, Erasmus University Medical Center, Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, The Netherlands
    J Clin Oncol 27:3126-32. 2009
    ..7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types...
  34. ncbi Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML
    Catriona H M Jamieson
    Division of Hematology, Stanford University School of Medicine, Stanford, Calif 94305 5323, USA
    N Engl J Med 351:657-67. 2004
    ..In normal mouse hematopoietic stem cells, the process of self-renewal involves the beta-catenin-signaling pathway. We investigated whether leukemic stem cells in CML also use the beta-catenin pathway for self-renewal...
  35. pmc Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity
    Amie S Corbin
    Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Portland, Oregon, USA
    J Clin Invest 121:396-409. 2011
    ..Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells...
  36. ncbi Dynamics of chronic myeloid leukaemia
    Franziska Michor
    Program for Evolutionary Dynamics, Department of Organismic and Evolutionary Biology, Department of Mathematics, Harvard University, Cambridge, Massachusetts 02138, USA
    Nature 435:1267-70. 2005
    ..We calculate the probability of developing imatinib resistance mutations and estimate the time until detection of resistance. Our model provides the first quantitative insights into the in vivo kinetics of a human cancer...
  37. ncbi Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet
    Michele Baccarani
    Department of Hematology Oncology, L and A Seragnoli, University of Bologna, Bologna, Italy
    J Clin Oncol 27:6041-51. 2009
    ....
  38. ncbi Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden
    Bengt Nilsson
    Department of Surgery, The Lundberg Laboratory for Cancer Research, Sahlgrenska Academy at the University of Göteborg, Goteborg, Sweden
    Cancer 103:821-9. 2005
    ..New treatment options mandate more accurate information regarding the incidence, prevalence, clinical behavior, and prognostic factors of GIST...
  39. ncbi The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo
    Sabine Ponader
    Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, TX 77230, USA
    Blood 119:1182-9. 2012
    ..Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent...
  40. ncbi Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia
    B J Druker
    Division of Hematology and Medical Oncology, Oregon Health Sciences University, Portland 97201, USA
    N Engl J Med 344:1031-7. 2001
    ..Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML...
  41. pmc Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)
    Juan M García-Martínez
    MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD15EH, Scotland, UK
    Biochem J 421:29-42. 2009
    ..Our results indicate that Ku-0063794 will be useful in delineating the physiological roles of mTOR and may have utility in treatment of cancers in which this pathway is inappropriately activated...
  42. pmc The specificities of protein kinase inhibitors: an update
    Jenny Bain
    Division of Signal Transduction Therapy, School of Life Sciences, MSI WTB complex, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, UK
    Biochem J 371:199-204. 2003
    ..33 microM) and p38-regulated/activated kinase (PRAK; IC(50)=1.0 microM)...
  43. ncbi Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies
    Michael C Heinrich
    Department of Medicine, Division of Hematology Oncology, Oregon Health and Science University, USA
    J Clin Oncol 20:1692-703. 2002
    ..In this review, we discuss the rationale for and development of KIT tyrosine kinase inhibitors for the treatment of human malignancies...
  44. pmc Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Gr
    Michael C Heinrich
    Division of Hematology Oncology, Department of Medicine and Cell and Developmental Biology, Portland Veterans Affairs Medical Center and Oregon Health and Science University Cancer Institute, Portland, OR 97239, USA
    J Clin Oncol 26:5360-7. 2008
    ..In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing...
  45. pmc The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy
    Lee A Honigberg
    Pharmacyclics, Sunnyvale, CA 94085 4521, USA
    Proc Natl Acad Sci U S A 107:13075-80. 2010
    ..These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway...
  46. pmc Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor
    Michael C Heinrich
    Division of Hematology Oncology, Department of Medicine and Cell and Developmental Biology, Portland Veterans Affairs Medical Center and Oregon Health and Science University Cancer Institute, Portland, OR 97239, USA
    J Clin Oncol 26:5352-9. 2008
    ..We evaluated the impact of primary and secondary kinase genotype on sunitinib activity...
  47. ncbi Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors
    Marcus Bantscheff
    Cellzome AG, Meyerhofstrasse 1, D 69117 Heidelberg, Germany
    Nat Biotechnol 25:1035-44. 2007
    ..The data suggest that our approach is a valuable tool for drug discovery...
  48. pmc Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765
    Sarah E M Herman
    Integrated Biomedical Science Graduate Program, The Ohio State University Medical Center, Columbus, OH, USA
    Blood 117:6287-96. 2011
    ..Based on these collective data, future efforts targeting BTK with the irreversible inhibitor PCI-32765 in clinical trials of CLL patients is warranted...
  49. ncbi MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma
    Michael A Milhollen
    Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA
    Blood 116:1515-23. 2010
    ..This work describes a novel mechanism of targeted NF-kappaB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-kappaB-dependent lymphomas...
  50. ncbi Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033
    Charles D Blanke
    Oregon Health and Science University Cancer Institute, 3181 SW Sam Jackson Park Rd, L 586, Portland, OR 97239, USA
    J Clin Oncol 26:626-32. 2008
    ....
  51. ncbi A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome
    Jan Cools
    Brigham and Women s Hospital and Harvard Medical School, Boston, USA
    N Engl J Med 348:1201-14. 2003
    ..Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause...
  52. ncbi Tyrosine kinases as targets for cancer therapy
    Daniela S Krause
    Molecular Oncology Research Institute, Division of Hematology Oncology, Tufts New England Medical Center, Boston, MA 02111, USA
    N Engl J Med 353:172-87. 2005
  53. ncbi A Phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer
    Michael Friedlander
    Prince of Wales Hospital, Randwick, Sydney, Australia
    Gynecol Oncol 119:32-7. 2010
    ..This phase II, open-label study evaluated oral pazopanib monotherapy in patients with low-volume recurrent ovarian cancer...
  54. ncbi Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl
    Ellen Weisberg
    Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Cancer Cell 7:129-41. 2005
    ..AMN107 is a promising new inhibitor for the therapy of CML and Ph+ ALL...
  55. ncbi Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study
    K A Papp
    Probity Medical Research, 135 Union Street East, Waterloo, ON N2J 1C4, Canada
    Br J Dermatol 167:668-77. 2012
    ..Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis...
  56. ncbi A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone
    Joel M Kremer
    Albany Medical College, Albany, New York 12206, USA
    Arthritis Rheum 64:970-81. 2012
    ....
  57. ncbi Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial
    George D Demetri
    Ludwig Center at Dana Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA
    Lancet 368:1329-38. 2006
    ....
  58. pmc Novel regulation of parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease
    Syed Z Imam
    Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78229, USA
    J Neurosci 31:157-63. 2011
    ..Moreover, inhibition of c-Abl offers new therapeutic opportunities for blocking PD progression...
  59. ncbi Pyrimidine salvage in Trypanosoma brucei bloodstream forms and the trypanocidal action of halogenated pyrimidines
    Juma A M Ali
    Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom
    Mol Pharmacol 83:439-53. 2013
    African trypanosomes are capable of both pyrimidine biosynthesis and salvage of preformed pyrimidines from the host...
  60. pmc Phase II trial of neoadjuvant/adjuvant imatinib mesylate for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumors: long-term follow-up results of Radiation Therapy Oncology Group 0132
    Dian Wang
    Medical College of Wisconsin, Milwaukee, WI, USA
    Ann Surg Oncol 19:1074-80. 2012
    ..We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy...
  61. ncbi Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia
    Stephen G O'Brien
    University of Newcastle, Newcastle, United Kingdom
    N Engl J Med 348:994-1004. 2003
    ..We compared the efficacy of imatinib with that of interferon alfa combined with low-dose cytarabine in newly diagnosed chronic-phase CML...
  62. ncbi Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation
    Alexandre Puissant
    INSERM 895, Team 2 Cell Death Differentiation and Cancer, Laboratoire d OncoHématologie, Centre Hospitalier Universitaire de Nice, Nice, France
    Cancer Res 70:1042-52. 2010
    ..We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy...
  63. pmc Sequence signatures of direct complementarity between mRNAs and cognate proteins on multiple levels
    Mario Hlevnjak
    Department of Structural and Computational Biology, Max F Perutz Laboratories, University of Vienna, Vienna 1030, Austria
    Nucleic Acids Res 40:8874-82. 2012
    ..of naturally occurring mRNA coding sequences with the propensity of cognate protein sequences to interact with pyrimidines. The latter is captured by polar requirement, a measure of solubility of amino acids in aqueous solutions of ..
  64. pmc Src inhibitors, PP2 and dasatinib, increase retinoic acid-induced association of Lyn and c-Raf (S259) and enhance MAPK-dependent differentiation of myeloid leukemia cells
    J Congleton
    Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA
    Leukemia 26:1180-8. 2012
    ..This is the first evidence suggesting SFK inhibitors enhance ATRA-induced differentiation through a possible feedback loop involving KSR1-scaffolded c-Raf and ERK complexed with Lyn and CK2...
  65. ncbi Characterization of Alisertib (MLN8237), an investigational small-molecule inhibitor of aurora A kinase using novel in vivo pharmacodynamic assays
    Mark G Manfredi
    Millennium Pharmaceuticals, Inc, Cambridge, 40 Landsdowne Street, Cambridge, MA 02139, USA
    Clin Cancer Res 17:7614-24. 2011
    ..Here, we describe preclinical characterization of alisertib (MLN8237), a selective AAK inhibitor, incorporating these novel pharmacodynamic assays...
  66. pmc Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study
    John C Araujo
    The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer 118:63-71. 2012
    ....
  67. pmc Blocking Hedgehog survival signaling at the level of the GLI genes induces DNA damage and extensive cell death in human colon carcinoma cells
    Tapati Mazumdar
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    Cancer Res 71:5904-14. 2011
    ..Taken together, these findings establish that inhibition of HH signaling at the level of the GLI genes downstream of Smo is critical in the induction of DNA damage in early S-phase, leading to cell death in human colon carcinoma cells...
  68. pmc A phase 2 trial of dasatinib in advanced melanoma
    Harriet M Kluger
    Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA
    Cancer 117:2202-8. 2011
    ..Dasatinib inhibits c-kit, PDGFβR, and EPHA2 and src kinases c-src, c-Yes, Lck, and Fyn. A phase 2 trial of dasatinib in melanoma was conducted to assess response rate (RR), progression-free survival (PFS), and toxicity...
  69. pmc The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer
    Tapati Mazumdar
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Oncotarget 2:638-45. 2011
    ....
  70. ncbi Phase II proof-of-concept study of pazopanib monotherapy in treatment-naive patients with stage I/II resectable non-small-cell lung cancer
    Nasser Altorki
    Weill Medical College, Cornell University, 525 East 68th St, New York, NY 10021, USA
    J Clin Oncol 28:3131-7. 2010
    ..This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC...
  71. pmc Drugging the PI3 kinome: from chemical tools to drugs in the clinic
    Paul Workman
    Cancer Research UK Centre for Cancer Therapeutics, Section of Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey, United Kingdom
    Cancer Res 70:2146-57. 2010
    ..The challenges and outlook for drugging the PI3 kinome are discussed in the more general context of the role of structural biology and chemical biology in innovative drug discovery...
  72. pmc Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors
    Jianming Zhang
    Dana Farber Cancer Institute, Harvard Medical School, Department of Cancer Biology, Seeley G Mudd Building 628, Boston, Massachusetts 02115, USA
    Nature 463:501-6. 2010
    ....
  73. ncbi Pyrazolo[1,5-a]pyrimidines: estrogen receptor ligands possessing estrogen receptor beta antagonist activity
    Dennis R Compton
    Department of Chemistry and Department of Molecular and Integrative Physiology, University of Illinois, 600 South Matthews Avenue, Urbana, Illinois 61801, USA
    J Med Chem 47:5872-93. 2004
    ....
  74. ncbi Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation
    Ying Wang
    Philipps Universität Giessen und Marburg, Standort Marburg, Klinik für Hämatologie, Onkologie und Immunologie, Marburg, Germany
    Blood 109:2147-55. 2007
    ..Inhibition of JAK-2 overcomes GM-CSF-induced IM and NI progenitor cell resistance, providing a rationale for the application of JAK-2 inhibitors to eradicate residual disease in CML...
  75. ncbi Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ
    James E Brownell
    Discovery, Millennium Pharmaceuticals, Inc, 40 Landsdowne Street, Cambridge, MA 02139, USA
    Mol Cell 37:102-11. 2010
    ..These findings reveal insights into the mechanism of E1s and suggest a general strategy for selective inhibition of UBL conjugation pathways...
  76. pmc A chemical and phosphoproteomic characterization of dasatinib action in lung cancer
    Jiannong Li
    Department of Thoracic Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA
    Nat Chem Biol 6:291-9. 2010
    ..The combined mass spectrometry-based approach described here provides a system-level view of dasatinib action in cancer cells and suggests both functional targets and a rationale for combinatorial therapeutic strategies...
  77. pmc Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study
    Keith C Bible
    Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
    Lancet Oncol 11:962-72. 2010
    ..We investigated the safety and efficacy of pazopanib...
  78. pmc Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia
    Abraham Martin
    INSERM U803, Orsay, France
    J Cereb Blood Flow Metab 30:230-41. 2010
    ..These results show that [(18)F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke...
  79. ncbi Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia
    Ruibao Ren
    Rosenstiel Basic Medical Sciences Research Center, MS029, Brandeis University, 415 South Street, Waltham, Massachusetts 02454 9110, USA
    Nat Rev Cancer 5:172-83. 2005
    ..What have clinical trials of imatinib and studies using mouse models for BCR-ABL leukaemogenesis taught us about the functions of BCR-ABL beyond its kinase activity, and how these functions contribute to CML pathogenesis?..
  80. ncbi Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction
    Mhairi Copland
    Division of Cancer Sciences and Molecular Pathology, University of Glasgow, UK
    Blood 107:4532-9. 2006
    ..These data confirm that dasatinib is more effective than IM within the CML stem cell compartment; however, the most primitive quiescent CML cells appear to be inherently resistant to both drugs...
  81. ncbi Regulation of androgen receptor activity by tyrosine phosphorylation
    Zhiyong Guo
    Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    Cancer Cell 10:309-19. 2006
    ....
  82. ncbi Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro
    Susan M Graham
    Department of Medicine, Royal Infirmary, Glasgow, Scotland
    Blood 99:319-25. 2002
    ..Despite dramatic short-term responses in vivo, such in vitro insensitivity to STI571, in combination with its demonstrated antiproliferative activity, could translate into disease relapse after prolonged therapy...
  83. ncbi Identification of candidate molecular markers predicting sensitivity in solid tumors to dasatinib: rationale for patient selection
    Fei Huang
    Departments of Clinical Discovery and Oncology Discovery, Bristol Myers Squibb Co, Princeton, NJ 08543, USA
    Cancer Res 67:2226-38. 2007
    ..Our results implicate that dasatinib may represent a valuable treatment option in this difficult-to-treat population. To test this hypothesis, clinical studies are now under way to determine the activity of dasatinib in these patients...
  84. pmc Reversal of experimental pulmonary hypertension by PDGF inhibition
    Ralph Theo Schermuly
    Department of Internal Medicine, Justus Liebig University Giessen, Giessen, Germany
    J Clin Invest 115:2811-21. 2005
    ..This regimen offers a unique novel approach for antire-modeling therapy in progressed pulmonary hypertension...
  85. ncbi Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis
    William J Sandborn
    Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093 0956, USA
    N Engl J Med 367:616-24. 2012
    ..These cytokines are integral to lymphocyte activation, function, and proliferation...
  86. pmc Rational design and characterization of a Rac GTPase-specific small molecule inhibitor
    Yuan Gao
    Division of Experimental Hematology, Children s Hospital Research Foundation, Cincinnati, OH 45229, USA
    Proc Natl Acad Sci U S A 101:7618-23. 2004
    ..Thus, NSC23766 constitutes a Rac-specific small-molecule inhibitor that could be useful to study the role of Rac in various cellular functions and to reverse tumor cell phenotypes associated with Rac deregulation...
  87. pmc Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells
    Cristian Bellodi
    University of Leicester, United Kingdom
    J Clin Invest 119:1109-23. 2009
    ..Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML...
  88. pmc Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study
    Kirk R Schultz
    Department of Pediatrics, Division of Hematology Oncology Bone Marrow Transplantation, University of British Columbia, B C s Children s Hospital, Vancouver, BC, V6H 3V4, Canada
    J Clin Oncol 27:5175-81. 2009
    ..Imatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups...
  89. pmc Induction of p21-dependent senescence by an NAE inhibitor, MLN4924, as a mechanism of growth suppression
    Lijun Jia
    Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B Medical Science I, Ann Arbor, MI 48109, USA
    Neoplasia 13:561-9. 2011
    ..Our study reveals a novel mechanism of MLN4924 action and showed that MLN4924 could be further developed as an effective anticancer agent by inducing apoptosis and irreversible senescence...
  90. ncbi Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans
    Brian P Rubin
    Department of Pathology, University of Washington Medical Center, Seattle, WA 98195, USA
    J Clin Oncol 20:3586-91. 2002
    ..We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate...
  91. ncbi Molecular pathobiology of gastrointestinal stromal sarcomas
    Christopher L Corless
    Department of Pathology, Oregon Health and Science University Cancer Institute, Portland, OR 97239, USA
    Annu Rev Pathol 3:557-86. 2008
    ....
  92. ncbi The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo
    Joel M Kremer
    Albany Medical College, Albany, New York, USA
    Arthritis Rheum 60:1895-905. 2009
    ....
  93. ncbi Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases
    Florence I Raynaud
    Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow and McElwain Laboratories, Sutton, Surrey, United Kingdom
    Cancer Res 67:5840-50. 2007
    ....
  94. ncbi Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial)
    Peter H Jones
    Baylor College of Medicine, 6565 Fannin Avenue, A 601, Houston, TX 77030, USA
    Am J Cardiol 92:152-60. 2003
    ..0 mmol/L was achieved by 79% to 92% in rosuvastatin groups compared with 52% to 81% in atorvastatin groups. Drug tolerability was similar across treatments...
  95. ncbi Src activation regulates anoikis in human colon tumor cell lines
    T Christopher Windham
    Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas, TX 77030, USA
    Oncogene 21:7797-807. 2002
    ..These results suggest that Src activation may contribute to colon tumor progression and metastasis in part by activating Akt-mediated survival pathways that decrease sensitivity of detached cells to anoikis...
  96. pmc Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors
    Gregory D Cuny
    Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham and Women s Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA
    Bioorg Med Chem Lett 18:4388-92. 2008
    ..g., plasma t(1/2)=1.6h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition...
  97. pmc Hedgehog signaling drives cellular survival in human colon carcinoma cells
    Tapati Mazumdar
    Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Cancer Res 71:1092-102. 2011
    ..Collectively, these results highlight the importance of Gli activation downstream of Smo as a therapeutic target in models of human colon carcinoma...
  98. pmc Applications of small molecule BMP inhibitors in physiology and disease
    Charles C Hong
    Division of Cardiovascular Medicine and Center for Inherited Heart Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, United States
    Cytokine Growth Factor Rev 20:409-18. 2009
    ..We also discuss several potential applications for small molecule BMP inhibitors, including stem cell manipulation, and the therapeutic modification of bone remodeling, heterotopic ossification, and iron homeostasis...
  99. pmc NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells
    Jie Jessie Lin
    Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA
    Cancer Res 70:10310-20. 2010
    ..Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge...
  100. ncbi Proteomic analysis of an imatinib-resistant K562 cell line highlights opposing roles of heat shock cognate 70 and heat shock 70 proteins in resistance
    Marion Pocaly
    U876 INSERM, Universite Victor Segalen Bordeaux 2, Hématopoïèse Leucémique et Cibles Thérapeutiques, Bordeaux, France
    Proteomics 8:2394-406. 2008
    ..In contrast, the induced decreased expression of Hsc70 was accompanied by a greater overexpression of Hsp70. This proteomic study therefore suggests opposing roles of Hsp70 and Hsc70 in imatinib resistance...
  101. ncbi Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study
    Oliver Ottmann
    Medizinische Klinik II, Johann Wolfgang Goethe Universitat, Frankfurt, Germany
    Blood 110:2309-15. 2007
    ..Dasatinib represents a safe and effective treatment option and an important therapeutic advance for patients with Ph-positive ALL. This trial was registered at www.clinicaltrials.gov as #CA180015...

Research Grants63

  1. SIMULATION OF PROTON AND HYDRIDE TRANSFER IN ENZYMES
    Sharon Hammes Schiffer; Fiscal Year: 2010
    ..This enzyme maintains tetrahydrofolate levels required to support the biosynthesis of purines, pyrimidines, and amino acids...
  2. Intra- and Extra-Chromosomal Probes for Mutagenesis by Carcinogens
    John M Essigmann; Fiscal Year: 2013
    ..containing 5-substituted cytosines (produced by oxidative stress), a series of N and 0-alkylated purines and pyrimidines (produced by alkylation and inflammation), and N2 and C8-purine aromatic amine adducts (produed by tobacco ..
  3. Molecular Modulation of Virus Capsid Assembly
    Adam Zlotnick; Fiscal Year: 2013
    ..several families of small molecules with assembly enhancing activity, in particular heteroaryldihydro- pyrimidines (HAPs)...
  4. Structural Biology of Purine and Pyrimidine Biosynthesis and Metabolism
    Steven E Ealick; Fiscal Year: 2012
    ..Catabolic pathways for the degradation of purines and pyrimidines have been previously described and structures are available for the key enzymes;however, recently a new pathway ..
  5. CARDIOMYOPATHY IN AIDS
    William Lewis; Fiscal Year: 2009
    ..Thymidine kinase 2 (TK2;phosphorylates pyrimidines intramitochondrially) is evaluated with "dominant negative" mutant TGs...
  6. Ultrafast Spectroscopic Methods to Probe Photodamage and Unfolding in Biopolymers
    David W McCamant; Fiscal Year: 2012
    ..This methodology will be applied to gain new understanding of the ultrafast dimerization of pyrimidines in DNA following excitation by UV light, as well as new fundamental understanding of the quantum mechanical ..
  7. DNA damage-induced regulation of base excision repair by dynamic localization
    NICHOLAS CHRISTOPHER BAUER; Fiscal Year: 2013
    ..An S. cerevisiae BER glycosylase which removes oxidized pyrimidines and is shared by nuclei and mitochondria, Ntg1, appears to be regulated through dynamic localization...
  8. Structure/function studies of nucleoside analog activating enzymes
    Arnon Lavie; Fiscal Year: 2009
    ..This inherent promiscuity also enables NAs of various structures (e.g. purines, pyrimidines, with modifications in the sugar, base, or both moieties) to be accepted as substrates...
  9. Novel HBV Therapeutic with Potential for Treatment of Drug-Resistant Infection
    Andrea Cuconati; Fiscal Year: 2013
    ..by applicant): This is a Phase II proposal to advance development of disubstituted tetrahydro-triazolo-pyrimidines (TTPs) as specific inhibitors of hepatitis B virus surface antigen (HBsAg) secretion in chronic infection...
  10. Corneal epithelial adhesion:morphology and biochemistry
    VICKERY E TRINKAUS-RANDALL; Fiscal Year: 2012
    ..Our lab has demonstrated that the active components that are released upon injury are purines and pyrimidines (nucleotides), which cause the propagation of a Ca2+ wave to neighboring cells...
  11. Phase II Environmentally greener, efficient, and safe synthetic platform for the
    PAUL MATTHEW HERRINTON; Fiscal Year: 2011
    ..Expand the portfolio of borylated pyridine derivatives and add quinolines, pyrazines, pyrimidines, diazenes, imidazoles, pyrazoles, oxazoles, etc. Produce oxidized products (e.g...
  12. Unnatural Base Pairs as DNA Bioprobes
    KATHERINE RADTKE; Fiscal Year: 2009
    ..The initial aims of this study are to (i) design, synthesize and characterize a series of extended pyrimidines and expanded purine nucleosides;(ii) to incorporate the unnatural nucleosides into DNA duplexes of varying ..
  13. LIPOPHILIC ANTIFOLATES AND AIDS OPPORTUNISTIC INFECTIONS
    Andre Rosowsky; Fiscal Year: 2004
    ..way to achieve selectivity is with 2,4-diamino-5-[(2-methoxy- and 3,4-dimethoxy-5-(C3-9)alkoxy)-benzyl] pyrimidines containing an acidic carboxyl or tetrazole group at the end of the O-alkyl side chain...
  14. MOLECULAR MECHANISMS OF PRPP-SYNTHETASE OVERACTIVITY
    Blake Roessler; Fiscal Year: 1991
    ..The formation of PRPP by this enzyme represents the first step in the de novo synthesis of purines, pyrimidines and pyridines...
  15. MOLECULAR MECHANISMS OF PRPP-SYNTHETASE OVERACTIVITY
    THOMAS PALELLA; Fiscal Year: 1990
    ..The formation of PRPP by this enzyme represents the first step in the de novo synthesis of purines, pyrimidines and pyridines...
  16. MECHANISM OF DIVICINE TOXICITY
    DAVID MC MILLAN; Fiscal Year: 1999
    ..of favism is not known, studies on the chemical reactivity of divicine have led to the hypothesis that these pyrimidines induce oxidative damage and initiate removal of sensitive red cells by splenic macrophages...
  17. DESIGN, SYNTHESIS AND STUDY OF IMPD INHIBITORS
    Wayne Anderson; Fiscal Year: 1993
    ..are proposed to examine the potential application of the MPA hexanoic acid side chain on selected purines, pyrimidines and related heterocycles...
  18. PHARMACOLOGY OF DIDEOXYNUCLEOSIDES IN SMALL INTESTINAL
    JESSIE AU; Fiscal Year: 1991
    ..3. Effect on normal nucleosides. Examine the effects of ddNS on the levels and metabolism of endogenous pyrimidines and purines (thymidine, deoxycytidine, deoxyinosine, deoxyadenosine and adenosine), and the incorporation of ..
  19. REACTIONS TO TRIMETHOPRIM-SULFAMETHOXAZOLE IN AIDS
    Manuel Lopez; Fiscal Year: 1990
    ..of Type I, II, and III hypersensitivity (measurement of class specific antibodies to several sulfonamides; pyrimidines; the sulfone, dapsone; and combinations of these drugs) and of Type IV cell mediated hypersensitivity (the ..
  20. Hybridization of Oligonucleotide Probes with Duplex DNA
    Maxim Frank Kamenetskii; Fiscal Year: 2005
    ..PNA openers with the extended triplex recognition will be used for mostly purine sites with few pyrimidines. A pseudocomplementary PNA modification, pcPNA, will be employed as an opener to substantially relieve the PD-..
  21. STRUCTURE SELECTIVITY RELATIONSHIPS OF ANTIBACTERIAL AGE
    CYNTHIA SELASSIE; Fiscal Year: 1992
    ..been based on a careful analysis of QSAR models derived from a study of approximately 68 2,4-diamino-5-X-benzyl pyrimidines III and their interactions with both chicken liver DHFR and E. coli DHFR...
  22. DISRUPTION OF DNA FUNCTION BY TG INCORPORATION
    Jonathan Maybaum; Fiscal Year: 1990
    Many anticancer and antiviral agents are analogs of purines or pyrimidines that are thought to act by being incorporated into DNA...
  23. DAMAGED DNA AND REPAIR
    Chulhee Kang; Fiscal Year: 1999
    ..The structural changes of DNA induced by UV, the dimerization of pyrimidines, are responsible in part for these harmful or lethal effects...
  24. ROLE AND FUNCTIONS OF PYRIMIDINES IN CANCER THERAPY
    Giuseppe Pizzorno; Fiscal Year: 2004
    ..Specific alterations of UPase genetic information will be achieved by: a) targeted disruption of UPase gene to nullify the UPase allele, and conversely, b) UPase gene transfer to elevate the UPase expression and activity in tissues. ..
  25. PRECISE ISOTOPE RATIO CHROMATOGRAPHY AND STABLE TRACERS
    JAMES BRENNA; Fiscal Year: 2004
    ..the in vivo turnover of long-lived components of long-lived cells in guinea pigs, particularly purines and pyrimidines, histone amino acids, and fatty acids in neural, liver, and adipose tissue...
  26. SELECTIVE DEPLETION OF ALKYLTRANSFERASE IN TUMOR CELLS
    M Dolan; Fiscal Year: 1999
    ..and metabolism of two classes of AGT inactivators, esterified derivatives of O6-benzylguanine and substituted pyrimidines. The ester prodrugs are much less potent against the pure AGT protein than their deesterified counterpart ..
  27. Uridine Supplementation for HIV lipoatrophy
    Grace McComsey; Fiscal Year: 2007
    ..mitochondrial dysfunction may inhibit dihydroorotate dehydrogenase and lead to depletion in natural pyrimidines; if the latter is true, providing exogenous uridine would reverse mitochondrial DNA content and function...
  28. PHOTOSENSITIZED PYRIMIDINE DIMER SPLITTING
    SETH ROSE; Fiscal Year: 1992
    Ultraviolet light in sunlight crosslinks pyrimidines in cellular deoxyribonucleic acid (DNA), producing pyrimidine dimers. These lesions in DNA are thought to be a potential cause of solar-UV-induced skin cancer...
  29. CLINICAL BIOCHEMICAL PHARMACOLOGY IN CANCER THERAPEUTICS
    Patrick Creaven; Fiscal Year: 1991
    ..of ovrcoming resistance to antimetabolites, both in solid tumors and in leukemia will focus on the fluorinated pyrimidines, with specific reference to approaches to the metabolic modulation of antimetabolites intracellularly to ..
  30. TRIPTYCENE ANALOGS--NOVEL BIFUNCTIONAL ANTICANCER DRUGS
    Jean Pierre Perchellet; Fiscal Year: 2004
    ..transport (effects on equilibrative and Na+-dependent transporters, bidirectional fluxes of purines and pyrimidines, competition with nucleoside transport probes), DNA (binding, intercalation, strand breakage and crosslinks, ..
  31. OXYGEN ACTIVATION BY PHENYLALANINE HYDROXYLASE
    JUNE AYLING; Fiscal Year: 1980
    ..Our recent findings, that appropriately substituted pyrimidines can serve as cofactors for the tetrahydrobiopterin dependent hydroxylases, has provided us with a new approach ..
  32. NOVEL URACILS, PYRIMIDINES, AZOLES AND PURINES
    Harold Shechter; Fiscal Year: 1991
    ....
  33. Enzymatic Mechanisms of Two Pyrimidine Decarboxylases
    Jeffrey Smiley; Fiscal Year: 2003
    ..substrate and inhibitor binding, which may include inhibition by pharmacologically significant 5-fluorinated pyrimidines. Adequate enzyme purification will also allow examination of the mode of binding of 5-nitrouracil using NMR ..
  34. INHIBITION OF PTERIDINE ENZYMES IN CANCER CHEMOTHERAPY
    JUNE AYLING; Fiscal Year: 1980
    ..Series of substituted pteridines and pyrimidines will be studied as cofactors and inhibitors of the three aromatic amino acid hydroxylases...
  35. SYNTHETIC MASKED NUCLEOSIDES FOR ANTICANCER STUDIES
    Kyoichi Watanabe; Fiscal Year: 1992
    ..or may be active in their own right, we will synthesize selected representatives of two classes of xylosyl-pyrimidines structurally related to these xylosyl lead nucleosides as potential antiviral and/or anticancer agents...
  36. Se-Derivatization of Functional RNAs for Structure Study
    Zhen Huang; Fiscal Year: 2004
    ..Unlike the conventional derivatization with bromine, which is limited to the 5-positions of the pyrimidines, selenium can be selectively incorporated into all nucleotide building blocks (A, C, G, U, and T, in both ..
  37. MOLECULAR BASIS OF ANTIGENIC SPECIFICITY
    Jindrich Kopecek; Fiscal Year: 1992
    ..In solution, the protein exhibited a base specificity for pyrimidines, with greater affinity for thymine than uracil...
  38. CHROMOSOMAL PROBES FOR MUTAGENESIS BY CARCINOGENS
    JOHN ESSIGMANN; Fiscal Year: 2007
    ..the mutagenic properties of less-well studied adducts, including DNA-DNA crosslinks and N1- and N3 substituted purines and pyrimidines, respectively, which could be important as progenitors to genetic change in humans.
  39. NOVEL NONINDUCIBLE THYMIDYLATE SYNTHASE INHIBITORS
    Aleem Gangjee; Fiscal Year: 2004
    ....
  40. Alpha Folate Receptor Mediated GARFTase Inhibitors as Selective Antitumor Agents
    Aleem Gangjee; Fiscal Year: 2010
    ....
  41. Single Agents with Designed Combination Chemotherapy Potential
    Aleem Gangjee; Fiscal Year: 2010
    ..abstract_text> ..
  42. Antitumor Antimitotics That Reverse Tumor Resistance
    Aleem Gangjee; Fiscal Year: 2010
    ..The study will also further define the mechanism of action of the novel series and could afford agents for clinical use. ..
  43. STRUCTURE BASED ANALOGS AS ANTIOPPORTUNISTIC AGENTS
    Aleem Gangjee; Fiscal Year: 2001
    ..The analogues synthesized will also be submitted for screening against tuberculosis (NIAID) parasitic diseases (WHO) and tumor cells in culture (NCI). ..
  44. Novel, P. jirovecii Specific Antipneumocystis Agents
    Aleem Gangjee; Fiscal Year: 2009
    ..These agents could be used alone or in combination to treat PCP thus providing novel agents against a new target. ..
  45. Novel Single, Dual and Multitargeted Inhibitors of RTKs
    Aleem Gangjee; Fiscal Year: 2007
    ..abstract_text> ..
  46. Third Generation Antiopportunistic Agents
    Aleem Gangjee; Fiscal Year: 2003
    ..Screening against tuberculosis (NIAID) and tumor cells in culture (NCI) is also proposed. ..
  47. REPAIR OF OXIC AND ANOXIC DNA DAMAGES
    YOKE KOW; Fiscal Year: 1999
    ..Damages such as dihydrothymine, a-anomers, cyclopurines and pyrimidines are only formed under anoxic conditions...
  48. OXIDATIVE DAMAGE REPAIR BY HUMAN ENDONUCLEASE III
    Rabindra Roy; Fiscal Year: 2001
    ..Among such oxidatively damaged bases, a series of toxic and mutagenic structurally diverse oxidized pyrimidines are repaired by endonuclease III (NTH), a glycosylase/lyase present in all species from bacteria through man...
  49. CARCINOGENIC PYRIMIDINES AT A MODEL REPLICATION FORK
    Lawrence Sowers; Fiscal Year: 2002
    ..The focus of this application on three oxidized pyrimidines, 5-formyluracil, 5-hydroxycytosine, and 5-hydroxyuracil...
  50. VIBRATIONAL SPECTROSCOPY OF BIOCHEMICAL MOLECULES
    WILLIS PERSON; Fiscal Year: 1992
    ..Related to this will be a theoretical and experimental study of changes in the spectra as purines and pyrimidines from self-associated dimers, complexes with small probe molecules (H20, CO, HCl, etc...
  51. DEVELOPMENT OF NEW ANTITUMOR AGENTS
    William Parker; Fiscal Year: 2005
    ..investigations of mechanism of action of new anticancer agents of the following classes: analogs of purines and pyrimidines and their nucleosides and nucleotides and analogs of penclomedine, a new agent evaluated in Phase I clinical ..
  52. Probes for Studies of Nucleotide-Binding Proteins
    MICHAEL GROZIAK; Fiscal Year: 2004
    ..most of the molecular topography of 5'-nucleotides: the C4'-C5' bond and the glycosidic one (C1'-N1 for pyrimidines and C1'-N9 for purines), and these are restricted simultaneously by the new tether...
  53. NEW STUDIES IN MOLECULAR RECOGNITION
    Steven Zimmerman; Fiscal Year: 1999
    ..A second project involves developing a host for GC and AT base-pairs that can recognize pyrimidines within a DNA triplex...
  54. DNA Sequencing using Nanopores
    Steven Benner; Fiscal Year: 2007
    ..prepare nucleoside triphosphates carrying different sized polyether dendrimers attached at the 5-position (for pyrimidines) and the 7-position (for 7-deazapurines); (d) use these triphosphates to synthesize modified DNA molecules...
  55. PHARMACOGENETIC FACTORS AND ADVERSE DRUG REACTIONS
    CHARLENE MCQUEEN; Fiscal Year: 1991
    ..The adducts that are formed by reacting HDZ with pyrimidines will be characterzied by their UV, NMR and mass spectra...
  56. STRUCTURAL STUDIES OF ADENOVIRUS-2 MRNA SYNTHESIS
    EDWARD ZIFF; Fiscal Year: 1980
    ..E) The heterogeneous 5' termini arise from a 2-6 base region with a fixed position relative to the Hogness Box. F) Within this region, purine termini are greatly favored over pyrimidines.
  57. Targeting malarial dihydroorotate dehydrogenase
    Margaret Phillips; Fiscal Year: 2003
    ..Unlike mammalian cells, the malaria parasite cannot salvage preformed pyrimidine bases or nucleosides, and pyrimidines are exclusively synthesized by the de novo pathway...
  58. RADIOSENSITIVITY AND CELLULAR MOLECULAR EFFECTS
    George Iliakis; Fiscal Year: 1991
    ..DNA damage to cytogenetic damage to cell death in mammalian cells grown in vitro in the presence of halogenated pyrimidines (HP) (mainly BrdUrd and IdUrd) at concentrations that are clinically achievable...
  59. GENE ACTION IN CULTURED HUMAN AND OTHER MAMMALIAN CELLS
    ROBERT KROOTH; Fiscal Year: 1980
    ..and biochemistry of mutant clones (of cultured erythroleukemic cells) which are resistant to halogenated pyrimidines. Finally, experiments are proposed which explore the biochemical mechanism whereby drugs that structurally ..
  60. CYTOTOXICITY AND RIBOSOMAL RNA MATURATION
    JOSEPH CORY; Fiscal Year: 1980
    The fluorinated pyrimidines are used in the treatment of cancer in man. The inhibition of the thymidylate synthetase step is a major site of action of these compounds...
  61. DNA SEQUENCING BY AF AND ST MICROSCOPY
    Edward Cox; Fiscal Year: 1992
    ..and (2) devise novel microscope tips designed to recognize the adsorption spectra of individual purines and pyrimidines. Our proposed new methods clamp the DNA to substrates using well-understood physical and chemical principles ..