Research Topics
| G ChiosisSummaryAffiliation: Memorial Sloan-Kettering Cancer Center Country: USA Publications
Research Grants
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Detail Information
Publications
Emerging Hsp90 inhibitors: from discovery to clinicG Chiosis
Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
Anticancer Agents Med Chem 6:1-8. 2006..This review intends to update the reader on the status of several existing and emerging classes of direct inhibitors of Hsp90 ATPase activity...
Heat shock protein 90: translation from cancer to Alzheimer's disease treatment?Wenjie Luo
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University and Fisher Foundation for Alzheimer s Disease, New York, NY 10021, USA
BMC Neurosci 9:S7. 2008..It will present experimentally demonstrated, but also hypothetical, roles that suggest Hsp90 can act as a regulator of pathogenic changes that lead to the neurodegenerative phenotype in Alzheimer's disease...- Development of purine-scaffold small molecule inhibitors of Hsp90Gabriela Chiosis
Department of Medicine and Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
Curr Cancer Drug Targets 3:371-6. 2003..The development of novel agents that lack the drawbacks of the natural products is thus necessary. Here we present an overview of such efforts with focus on a new class of purine-scaffold Hsp90 inhibitors developed by rational design... - Heat shock protein 90 in neurodegenerative diseasesWenjie Luo
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Mol Neurodegener 5:24. 2010..This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases... - Hsp90: the vulnerable chaperoneGabriela Chiosis
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Drug Discov Today 9:881-8. 2004..This review will discuss several emerging classes of Hsp90 inhibitors and their modes of action... - 17AAG: low target binding affinity and potent cell activity--finding an explanationGabriela Chiosis
Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
Mol Cancer Ther 2:123-9. 2003..We suggest that in the clinic, micromolar concentrations of 17AAG must accumulate in the tumor cells to achieve antitumor effects in patients comparable with ones achieved in tissue culture settings... - Small molecule microarrays: from proteins to mammalian cells - are we there yet?Gabriela Chiosis
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Trends Biotechnol 23:271-4. 2005..This technological improvement opens the door for using SMMs to perform high-throughput screens in mammalian cells... - Targeting chaperones in transformed systems--a focus on Hsp90 and cancerGabriela Chiosis
Programme in Molecular Pharmacology and Chemistry, Department of Medicine, Memorial Sloan Kettering Cancer Center, Box 482, New York, NY 10021, USA
Expert Opin Ther Targets 10:37-50. 2006..In this review, the authors present the current understanding on the relevance and possibility of translating Hsp90 inhibitors into therapeutic agents in cancer therapy... - Discovery and development of purine-scaffold Hsp90 inhibitorsGabriela Chiosis
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
Curr Top Med Chem 6:1183-91. 2006..One such emerging class is the purine-scaffold series. This review intends to inform the reader on efforts ranging from the discovery to their clinical translation... - Synthesis of Hsp90 dimerization modulatorsGabriela Chiosis
Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Bioorg Med Chem Lett 16:3529-32. 2006..These agents may represent useful tools to study the importance of N-terminal dimerization and also to determine subunit interface(s) in Hsp90... - Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agentsGabriela Chiosis
Memorial Sloan Kettering Cancer Center, Department of Medicine and Program in Molecular Pharmacology and Chemistry, 1275 York Avenue, New York, NY 10021, USA
Curr Opin Investig Drugs 7:534-41. 2006..This review discusses the modalities that may interfere with this chaperone's function and describes the status of existing and emerging Hsp90 inhibitor classes... - Purine-scaffold Hsp90 inhibitorsGabriela Chiosis
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
IDrugs 9:778-82. 2006..This feature describes the purine-scaffold class of Hsp90 inhibitors, focusing on research efforts from the discovery stage to the clinical translation of such compounds... - Identification of a geldanamycin dimer that induces the selective degradation of HER-family tyrosine kinasesF F Zheng
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
Cancer Res 60:2090-4. 2000..GMD-4c could be useful in the treatment of carcinomas dependent on HER-kinases... - A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cellsG Chiosis
Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
Chem Biol 8:289-99. 2001..e. steroid receptors, Her2, Raf). We have used the structural features of this pocket to design a small molecule inhibitor of Hsp90... - Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90Maria Vilenchik
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA
Chem Biol 11:787-97. 2004..Concentrations achieved in vivo in tumors lead to single-agent anti-tumor activity at non-toxic doses... - Total synthesis as a resource in the discovery of potentially valuable antitumor agents: cycloproparadicicolKana Yamamoto
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10021, USA
Angew Chem Int Ed Engl 42:1280-4. 2003 - LY294002-geldanamycin heterodimers as selective inhibitors of the PI3K and PI3K-related familyG Chiosis
Department of Molecular Oncogenesis, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Bioorg Med Chem Lett 11:909-13. 2001..Several LY294002-GM heterodimers were synthesized with the intent of modulating their activity in the presence of hsp90 and thereby creating selective inhibitors of PI3K and PI3K-related family... - Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancerAnna Rodina
Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
Nat Chem Biol 3:498-507. 2007..These results provide important evidence for a transformation-specific interplay between chaperones in regulating apoptosis in malignant cells... - Assay strategies for the discovery and validation of therapeutics targeting Brugia pahangi Hsp90Tony Taldone
Department of Molecular Pharmacology and Chemistry, Sloan Kettering Institute, New York, New York, United States of America
PLoS Negl Trop Dis 4:e714. 2010..The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target... - Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 functionAndrea D Basso
Program in Pharmacology, Weill Graduate School of Medical Sciences, Cornell University and the Program in Cell Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
J Biol Chem 277:39858-66. 2002..Thus, transduction of growth factor signaling via the Akt and Raf pathways requires functional Hsp90 and can be coordinately blocked by its inhibition... - Development of a purine-scaffold novel class of Hsp90 binders that inhibit the proliferation of cancer cells and induce the degradation of Her2 tyrosine kinaseGabriela Chiosis
Program in Cell Biology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10021, USA
Bioorg Med Chem 10:3555-64. 2002..Induces the degradation of Her2 tyrosine kinase and arrests the MCF-7 breast cancer cell line at low micromolar concentrations (IC50=2 microM)... - Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90Laura Llauger
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
J Med Chem 48:2892-905. 2005.... - Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90Huazhong He
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
J Med Chem 49:381-90. 2006..When administered in vivo to mice bearing MDA-MB-468 human breast cancer xenografted tumors, these agents result in pharmacologically relevant concentrations and, accordingly, in modulation of Hsp90-client proteins in tumors... - Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple-negative breast cancer modelsEloisi Caldas-Lopes
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Proc Natl Acad Sci U S A 106:8368-73. 2009..The results identify Hsp90 as a critical and multimodal target in this most difficult to treat breast cancer subtype and support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving patients with TNBC... - Targeting Hsp90: small-molecule inhibitors and their clinical developmentTony Taldone
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Curr Opin Pharmacol 8:370-4. 2008.... - Synthesis of a red-shifted fluorescence polarization probe for Hsp90Kamalika Moulick
Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Bioorg Med Chem Lett 16:4515-8. 2006..The synthesis of a red-shifted cy3B-GM ligand and its evaluation as a fluorescence polarization probe for Hsp90 is presented... - Assay for isolation of inhibitors of her2-kinase expressionGabriela Chiosis
Program in Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Methods Mol Biol 486:139-49. 2009..Here, we describe a hybrid western-blotting and enzyme-linked immunosorbent assay (ELISA) designed to identify in low- to medium-throughput format noncytotoxic compounds that reduce expression of Her2 protein... 
Development and application of Hsp90 inhibitorsDavid B Solit
Department of Medicine and the Human Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, United States
Drug Discov Today 13:38-43. 2008..It will also update the reader on the preclinical development and clinical translation of Hsp90 inhibitors...- Purine-scaffold Hsp90 inhibitorsTony Taldone
Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Curr Top Med Chem 9:1436-46. 2009..Their potential towards neurodegenerative diseases will also be touched upon... - Development of a fluorescence polarization assay for the molecular chaperone Hsp90Joungnam Kim
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
J Biomol Screen 9:375-81. 2004..These data demonstrate that the Hsp90-FP-based assay can be used for high-throughput screening in aiding the identification of novel Hsp90 inhibitors... - Synthesis of novel fluorescent probes for the molecular chaperone Hsp90Laura Llauger-Bufi
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Bioorg Med Chem Lett 13:3975-8. 2003..Here we report the synthesis and characterization of two fluorescent Hsp90 inhibitors and probe their use in an Hsp90 fluorescent polarization assay... - Selective cleavage of D-Ala-D-Lac by small molecules: re-sensitizing resistant bacteria to vancomycinG Chiosis
Department of Chemistry, Columbia University, New York, NY 10027, USA
Science 293:1484-7. 2001..These molecules were tested in combination with vancomycin and were found to re-sensitize vancomycin-resistant bacteria to the antibiotic... - Measuring the pharmacodynamic effects of a novel Hsp90 inhibitor on HER2/neu expression in mice using Zr-DFO-trastuzumabJason P Holland
Radiochemistry Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, Sloan Kettering Cancer Center, New York, New York, United States of America
PLoS ONE 5:e8859. 2010..In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted... - Tumor selectivity of Hsp90 inhibitors: the explanation remains elusiveGabriela Chiosis
Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
ACS Chem Biol 1:279-84. 2006..They spotlight the higher affinity of ansamycins' hydroquinone over the quinone form for Hsp90 and further discuss its possible contribution to ansamycins' tumor selectivity... - Discovery and development of heat shock protein 90 inhibitorsTony Taldone
Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 482, New York, NY 10021, USA
Bioorg Med Chem 17:2225-35. 2009..This review will discuss the discovery of these different classes, as well as their development as potential clinical agents... - General method for the synthesis of 8-arylsulfanyl adenine derivativesHuazhong He
Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
J Org Chem 69:3230-2. 2004..We report a general method for the synthesis of 8-arylsulfanyl adenine derivatives using a mild protocol of coupling 8-mercaptoadenine with a variety of aryl iodides... - Kaiso contributes to DNA methylation-dependent silencing of tumor suppressor genes in colon cancer cell linesEloisi C Lopes
Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Cancer Res 68:7258-63. 2008..Because Kaiso inactivation sensitized colon cancer cell lines to chemotherapy, it is possible that therapeutic targeting of Kaiso could improve the efficacy of current treatment regimens... - Microwave-assisted one step synthesis of 8-arylmethyl-9H-purin-6-aminesHui Tao
Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 482, New York, NY 10021, USA
Bioorg Med Chem Lett 19:415-7. 2009..We discuss the applicability as well as the limitations of this method towards the creation of a large chemical diversity in the 8-arylmethyl-9H-purin-6-amine series... - Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathiesWenjie Luo
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University and Fisher Foundation for Alzheimer s Disease, New York, NY 10021, USA
Proc Natl Acad Sci U S A 104:9511-6. 2007..The results identify important roles played by Hsp90 in maintaining and facilitating the degenerative phenotype in these diseases and provide a common principle governing cancer and neurodegenerative diseases... - Microtiter cell-based assay for detection of agents that alter cellular levels of Her2 and EGFRHenri Huezo
Program in Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
Chem Biol 10:629-34. 2003..The method gives results comparable to Western blot, but it is faster, less labor intensive, and amenable to high throughput... - A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomasLeandro C Cerchietti
Division of Hematology and Oncology, Weill Cornell Medical College of Cornell University, New York, New York, USA
Nat Med 15:1369-76. 2009..PU-H71 also induced cell death in primary human DLBCL specimens... - HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humansSachie Marubayashi
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
J Clin Invest 120:3578-93. 2010..Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN... - Design of a fluorescence polarization assay platform for the study of human Hsp70Yanlong Kang
Program in Molecular Pharmacology and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
Bioorg Med Chem Lett 18:3749-51. 2008..Here, we present a novel assay platform based on fluorescence polarization that is suitable for investigating the yet elusive molecular mechanics of human Hsp70 allosteric regulation... - Structural and quantum chemical studies of 8-aryl-sulfanyl adenine class Hsp90 inhibitorsRobert M Immormino
Hauptman-Woodward Medical Research Institute, Buffalo, New York 14203, USA
J Med Chem 49:4953-60. 2006..The predictive nature of the calculations has allowed the exploration of additional derivatives based on the 8-aryl adenine scaffold... - Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulatorsHaley Hieronymus
The Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
Cancer Cell 10:321-30. 2006..Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy... - Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteinsCeline Didelot
Inserm UMR 866, Faculty of Medicine and Pharmacy, 7 Boulevard Jeanne d Arc, 21049 Dijon, France
Curr Med Chem 14:2839-47. 2007..This review will discuss this different and often paradoxical approaches in cancer therapy based on the dual role of Hsps, protective/tumorigenic versus immunogenic... - Molecular imaging of the efficacy of heat shock protein 90 inhibitors in living subjectsCarmel T Chan
Department of Radiology, Stanford University School of Medicine, Stanford, California 94305 5427, USA
Cancer Res 68:216-26. 2008.... - Identification of novel quaternary domain interactions in the Hsp90 chaperone, GRP94Feixia Chu
Mass Spectrometry Facility, University of California, San Francisco, California 94143, USA
Protein Sci 15:1260-9. 2006..These results identify a compact, intertwined quaternary conformation of native GRP94 and suggest that intersubunit N+M interactions are integral to the structural biology of Hsp90... - The chaperone activity of heat shock protein 90 is critical for maintaining the stability of leucine-rich repeat kinase 2Lizhen Wang
Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892, USA
J Neurosci 28:3384-91. 2008..Therefore, inhibition of LRRK2 kinase activity can be achieved by blocking Hsp90-mediated chaperone activity and Hsp90 inhibitors may serve as potential anti-PD drugs... - BCR-ABL point mutants isolated from patients with imatinib mesylate-resistant chronic myeloid leukemia remain sensitive to inhibitors of the BCR-ABL chaperone heat shock protein 90Mercedes E Gorre
Department of Medicine and Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA 900095 1678, USA
Blood 100:3041-4. 2002..These data support clinical investigations of 17-AAG in imatinib mesylate-resistant Ph(+) leukemias... - High-throughput screening fluorescence polarization assay for tumor-specific Hsp90Yuhong Du
Department of Pharmacology, Emory University School of Medicine and Emory Chemical Biology Discovery Center, Atlanta, Georgia, USA
J Biomol Screen 12:915-24. 2007..A study using more than 15,000 compounds from the National Institutes of Health Molecular Libraries Screening Center Network was performed to validate its performance in a high-throughput screening format... - New arylthioindoles: potent inhibitors of tubulin polymerization. 2. Structure-activity relationships and molecular modeling studiesGabriella De Martino
Istituto Pasteur--Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, , Piazzale Aldo Moro 5, I-00185 Rome, Italy
J Med Chem 49:947-54. 2006..Dynamics simulation studies correlate well with the observed experimental data. Furthermore, from careful analysis of the biological and in silico data, we can now hypothesize a basic pharmacophore for this class of compounds... - Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulatorsJeffrey L Brodsky
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260 USA
Curr Top Med Chem 6:1215-25. 2006..Finally, we will review the recent discovery of small molecules that alter Hsp70 expression and function... - Vancomycin resistance: occurrence, mechanisms and strategies to combat itIvo G Boneca
Unité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur, 25 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France
Expert Opin Ther Targets 7:311-28. 2003..Whilst most of these agents are still in clinical or preclinical development, some have entered the clinic and currently represent the only option for treating vancomycin-resistant enterococci (VRE)... - Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein 90 (Hsp90): Synthesis, biology, and molecular modelingThota Ganesh
Chemical Biology Discovery Center, 1510 Clifton Road, Emory University, Atlanta, GA 30322, USA
Bioorg Med Chem 16:6903-10. 2008..These compounds represent a new class of Hsp90 inhibitors with simple chemical structures...
Research Grants
- Development of HTS assays probing Hsp90 inhibition (RMI)Gabriela Chiosis; Fiscal Year: 2004..Hits resulted from the FP assay will be tested for Her2 degradation potency in the breast cancer cell line SKBr3. Highest ranking compounds in both screens will be taken for further testing in follow-up research programs. ..
- Isolation of Inhibitors of Her-Kinase Expression (RMI)Gabriela Chiosis; Fiscal Year: 2005..To our knowledge, this has not been accomplished, and we believe that we are uniquely positioned to initiate this goal. ..
- FP Assay for Isolation of Hsp90 Inhibitors (RMI)Gabriela Chiosis; Fiscal Year: 2005....
- Assays for rapid identification of Hsp70 modulatorsGabriela Chiosis; Fiscal Year: 2007....
- Hsp90 inhibitors as suppressors of protein misfolding toxicityGabriela Chiosis; Fiscal Year: 2007..In conclusion, Hsp90- interfering drugs represent a potential novel class of drugs to promote the survival of neurons and open up a promising approach to the treatment of neurodegenerative diseases. ..