L T Vassilev

Summary

Affiliation: F. Hoffmann-La Roche Ltd

Publications

  1. ncbi request reprint Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells
    Steven J Berthel
    Discovery Chemistry, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Anticancer Drugs 13:359-66. 2002
  2. ncbi request reprint Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation
    Mingxuan Xia
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, New Jersey 07110, USA
    Cell Cycle 7:1604-12. 2008
  3. ncbi request reprint Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis
    Thelma Thompson
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, 340 Kingsland St, Nutley, NJ 07110, USA
    J Biol Chem 279:53015-22. 2004
  4. ncbi request reprint High-throughput screening for inhibitors of the Cks1-Skp2 interaction
    Kuo Sen Huang
    Discovery Technologies, Hoffmann La Roche, Inc, Nutley, New Jersey, USA
    Methods Enzymol 399:717-28. 2005
  5. pmc Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
    Christian Tovar
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Proc Natl Acad Sci U S A 103:1888-93. 2006
  6. pmc MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer
    Christian Tovar
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Mol Cancer 10:49. 2011
  7. pmc Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3
    Baoying Huang
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Aging (Albany NY) 1:845-54. 2009
  8. ncbi request reprint Cell cycle synchronization at the G2/M phase border by reversible inhibition of CDK1
    Lyubomir T Vassilev
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, New Jersey 07110, USA
    Cell Cycle 5:2555-6. 2006
  9. ncbi request reprint MDM2 inhibitors for cancer therapy
    Lyubomir T Vassilev
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Trends Mol Med 13:23-31. 2007
  10. pmc Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1
    Lyubomir T Vassilev
    Departments of Discovery Oncology and Discovery Chemistry, Roche Research Center, Hoffmann La Roche, Inc, Nutley, NJ 07110, USA
    Proc Natl Acad Sci U S A 103:10660-5. 2006

Collaborators

Detail Information

Publications33

  1. ncbi request reprint Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells
    Steven J Berthel
    Discovery Chemistry, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Anticancer Drugs 13:359-66. 2002
    ..Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs...
  2. ncbi request reprint Elevated MDM2 boosts the apoptotic activity of p53-MDM2 binding inhibitors by facilitating MDMX degradation
    Mingxuan Xia
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, New Jersey 07110, USA
    Cell Cycle 7:1604-12. 2008
    ....
  3. ncbi request reprint Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis
    Thelma Thompson
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, 340 Kingsland St, Nutley, NJ 07110, USA
    J Biol Chem 279:53015-22. 2004
    ..We conclude that p53 phosphorylation on six major serine sites is not required for activation of p53 target genes or biological responses in vivo...
  4. ncbi request reprint High-throughput screening for inhibitors of the Cks1-Skp2 interaction
    Kuo Sen Huang
    Discovery Technologies, Hoffmann La Roche, Inc, Nutley, New Jersey, USA
    Methods Enzymol 399:717-28. 2005
    ....
  5. pmc Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy
    Christian Tovar
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Proc Natl Acad Sci U S A 103:1888-93. 2006
    ..Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction...
  6. pmc MDM2 antagonists boost antitumor effect of androgen withdrawal: implications for therapy of prostate cancer
    Christian Tovar
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Mol Cancer 10:49. 2011
    ..Here, we test this hypothesis in vitro and in vivo using the MDM2 antagonist, nutlin-3 and the p53 wild-type prostate cancer cell line, LNCaP...
  7. pmc Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3
    Baoying Huang
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Aging (Albany NY) 1:845-54. 2009
    ....
  8. ncbi request reprint Cell cycle synchronization at the G2/M phase border by reversible inhibition of CDK1
    Lyubomir T Vassilev
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, New Jersey 07110, USA
    Cell Cycle 5:2555-6. 2006
    ..RO-3306 arrested cells enter mitosis rapidly after release from the G2 block thus allowing for isolation of mitotic cells without microtubule poisons. RO-3306 represents a new molecular tool for studying CDK1 function in human cells...
  9. ncbi request reprint MDM2 inhibitors for cancer therapy
    Lyubomir T Vassilev
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Trends Mol Med 13:23-31. 2007
    ..Here, the new developments in the quest for pharmacological p53 activators are reviewed with an emphasis on small-molecule inhibitors of the p53-MDM2 interaction...
  10. pmc Selective small-molecule inhibitor reveals critical mitotic functions of human CDK1
    Lyubomir T Vassilev
    Departments of Discovery Oncology and Discovery Chemistry, Roche Research Center, Hoffmann La Roche, Inc, Nutley, NJ 07110, USA
    Proc Natl Acad Sci U S A 103:10660-5. 2006
    ..Although CDK1 inhibition for up to 24 h is well tolerated, longer exposure to the inhibitor induces apoptosis in tumor cells, suggesting that selective CDK1 inhibitors may have utility in cancer therapy...
  11. ncbi request reprint Cell-based screening approach for antitumor drug leads which exploits sensitivity differences between normal and cancer cells: identification of two novel cell-cycle inhibitors
    L T Vassilev
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Anticancer Drug Des 16:7-17. 2001
    ..Two of the compounds representing novel mitotic inhibitors with in vivo potency against established breast cancer xenografts (MDA-MB-435) are reported here...
  12. ncbi request reprint p53 Activation by small molecules: application in oncology
    Lyubomir T Vassilev
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, New Jersey 07110, USA
    J Med Chem 48:4491-9. 2005
  13. ncbi request reprint In vivo activation of the p53 pathway by small-molecule antagonists of MDM2
    Lyubomir T Vassilev
    Department of Discovery Oncology, Roche Research Center, Hoffmann La Roche, Inc, Nutley, NJ 07110, USA
    Science 303:844-8. 2004
    ..These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice...
  14. doi request reprint Pharmacologic p53 activation blocks cell cycle progression but fails to induce senescence in epithelial cancer cells
    Baoying Huang
    Discovery Oncology, Hoffmann La Roche, Inc, Nutley, NJ 07110, USA
    Mol Cancer Res 7:1497-509. 2009
    ..However, elevated expression of several inflammatory cytokines in cancer cells with nutlin-induced senescence-like phenotype suggests a possible in vivo benefit of p53-activating therapies...
  15. ncbi request reprint Activation of p53 by MDM2 antagonists can protect proliferating cells from mitotic inhibitors
    Daisy Carvajal
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, New Jersey 07110, USA
    Cancer Res 65:1918-24. 2005
    ..Second, pretreatment with MDM2 antagonists before chemotherapy of tumors with mutant p53 may offer a partial protection to proliferating normal tissues...
  16. ncbi request reprint Targeting protein-protein interactions for cancer therapy
    David C Fry
    Structural Chemistry Group, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    J Mol Med (Berl) 83:955-63. 2005
    ..The analysis focuses primarily on the structural characteristics of the participating binding sites, particularly the dimensions of the sites. Known ligands are also examined, especially with regard to their druglikeness...
  17. doi request reprint Synthesis and evaluation of pyrido-thieno-pyrimidines as potent and selective Cdc7 kinase inhibitors
    Chunlin Zhao
    Discovery Chemistry, Research Center, Roche, Nutley, NJ 07110, USA
    Bioorg Med Chem Lett 19:319-23. 2009
    ..Synthesis of a focused pyrido-thieno-pyrimidine library yielded potent and selective Cdc7 inhibitors with antiproliferative activity against cancer cells in vitro. Their synthesis and SAR data are presented herein...
  18. ncbi request reprint Small-molecule antagonists of p53-MDM2 binding: research tools and potential therapeutics
    Lyubomir T Vassilev
    Roche Research Center, Hoffman La Roche Inc, Nutley, New Jersey 07110, USA
    Cell Cycle 3:419-21. 2004
    ..Their potent activity against osteosarcoma xenografts suggests that MDM2 antagonists may have clinical utility in the treatment of tumors with wild-type p53...
  19. ncbi request reprint A generic time-resolved fluorescence assay for serine/threonine kinase activity: application to Cdc7/Dbf4
    Kui Xu
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    J Biochem Mol Biol 36:421-5. 2003
    ..Using this approach, we developed an assay for Cdc7/Dbf4 kinase activity, determined the K(m) for ATP, and identified rottlerin as a non-ATP competitive inhibitor of this enzyme...
  20. ncbi request reprint Synthesis and activity of quinolinyl-methylene-thiazolinones as potent and selective cyclin-dependent kinase 1 inhibitors
    Shaoqing Chen
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Bioorg Med Chem Lett 17:2134-8. 2007
    ..Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents...
  21. doi request reprint p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation
    M Xia
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Oncogene 30:346-55. 2011
    ..Taken together our results suggest that p21 induction does not affect the apoptotic response to nongenotoxic p53 activation...
  22. pmc 1,25-dihydroxyvitamin D3 enhances the apoptotic activity of MDM2 antagonist nutlin-3a in acute myeloid leukemia cells expressing wild-type p53
    Thelma Thompson
    Discovery Oncology, Roche Research Center, Hoffmann La Roche, Inc, Nutley, New Jersey, USA
    Mol Cancer Ther 9:1158-68. 2010
    ....
  23. pmc Protein-protein interactions involved in the recognition of p27 by E3 ubiquitin ligase
    Kui Xu
    Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Biochem J 371:957-64. 2003
    ..Cks1 does not bind directly to the p27 phosphopeptide or to Skp1, which confirms its suggested role as an allosteric effector of Skp2...
  24. ncbi request reprint Development of E3-substrate (MDM2-p53)-binding inhibitors: structural aspects
    David C Fry
    Structural Chemistry Group, Hoffmann La Roche, Inc, Nutley, New Jersey, USA
    Methods Enzymol 399:622-33. 2005
    ..These tools are likely to be useful in any attempt to find and develop druglike compounds that modulate the function of a protein-protein interaction...
  25. ncbi request reprint Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation
    Hong Yang
    Discovery Oncology, Roche Research Center, Hoffmann La Roche Inc, Nutley, NJ 07110, USA
    Mol Cancer Ther 2:1023-9. 2003
    ..Estimation of MIC-1 concentration, both in vivo and in vitro, represents a novel tool for the study of p53 pathway and development of p53-activating therapeutics...
  26. ncbi request reprint Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin
    Alejo Efeyan
    Molecular Oncology Program, Spanish National Cancer Research Center CNIO, Madrid, Spain
    Cancer Res 67:7350-7. 2007
    ..Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a...
  27. ncbi request reprint Enhanced tumor cell kill by combined treatment with a small-molecule antagonist of mouse double minute 2 and adenoviruses encoding p53
    Harm C A Graat
    Department of Medical Oncology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands
    Mol Cancer Ther 6:1552-61. 2007
    ..These findings suggest that Nutlins are promising compounds to be combined with p53 gene therapy and oncolytic virotherapy for cancer...
  28. ncbi request reprint Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors
    Mikhail V Blagosklonny
    New York Medical College, Valhalla, New York 12208, USA
    Cancer Res 65:7386-92. 2005
    ..In a broader perspective, this shows how selectivity may be achieved by targeting a non-cancer-specific target, such as histone deacetylases, in the presence of a cancer-specific alteration, such as mutant p53...
  29. ncbi request reprint Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma
    Thorsten Stühmer
    Department of Internal Medicine II, Division of Hematology and Oncology, University Clinics Würzburg, Germany
    Blood 106:3609-17. 2005
    ..Therefore, MDM2 antagonists may offer a new treatment option for this disease...
  30. ncbi request reprint MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells
    Llorenç Coll-Mulet
    Departament de Ciències Fisiològiques II, IDIBELL Universitat de Barcelona, Campus de Bellvitge, Pavelló de Govern, 4a planta, E 08907 L Hospitalet de Llobregat, Barcelona, Spain
    Blood 107:4109-14. 2006
    ..These results suggest that MDM2 antagonists alone or in combination with chemotherapeutic drugs may offer a new treatment option for B-CLL...
  31. pmc Triptolide sensitizes AML cells to TRAIL-induced apoptosis via decrease of XIAP and p53-mediated increase of DR5
    Bing Z Carter
    The University of Texas M D Anderson Cancer Center, Housto 77030, USA
    Blood 111:3742-50. 2008
    ..Thus, the combination of triptolide and TRAIL may provide a novel strategy for treating AML by overcoming critical mechanisms of apoptosis resistance...
  32. doi request reprint p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism
    Andrew J Steele
    Department of Hematology, Royal Free and University College Medical School, London, United Kingdom
    Blood 112:3827-34. 2008
    ..Therefore, strategies that block up-regulation of p53-mediated transcription may be of value in enhancing apoptosis induction of CLL cells by p53-elevating drugs...
  33. pmc MDM2 antagonists induce p53-dependent apoptosis in AML: implications for leukemia therapy
    Kensuke Kojima
    Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Unit 448, Houston, TX 77030, USA
    Blood 106:3150-9. 2005
    ..p53 activation by targeting the p53-MDM2 interaction might offer a novel therapeutic strategy for AML that retain wild-type p53...