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Abstract
Grant Number: 1R03MH076499-01 Project Title: FP Assay for Isolation of Hsp90 Inhibitors (RMI)
PI Information: Name Title CHIOSIS, GABRIELA chiosisg@mskcc.org Abstract: DESCRIPTION (provided by applicant): The long-term goal of this initiative is to identify novel Hsp90 inhibitors with use in cancer therapy and in the treatment of neurodegenerative diseases. The goal of the current effort is to translate our Hsp90 fluorescence polarization assay to MLSCN centers. This assay probes the competitive binding of red-shifted cy3B-labeled geldanamycin to Hsp90 from cell lysates. Funding for the development of the assay has been provided in part by R03 NS050838-01; Chiosis, G (PI). Hsp90 is a chaperone with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Recent evidence suggests additional applications of Hsp90 inhibitors in neurodegenerative diseases, nerve injuries, inflammation and infection. Several natural products that inactivate Hsp90 function have anti-tumor effects in in vitro and in vivo models of cancer. However, due to the role of Hsp90 in normal cellular homeostasis, it remained unclear whether Hsp90 inhibitors will be sufficiently specific for use as therapeutic agents. Early clinical results with 17AAG, the first Hsp90 inhibitor to enter clinical trials, suggest that these fears may be unfounded. These studies confirm that Hsp90 is a promising target for novel cancer therapeutics and pave the road for the introduction of Hsp90 inhibitors in the clinic. The potential of Hsp90 inhibitors as therapeutics in other diseases has been less explored due to limitations with the current inhibitors (i.e. 17AAG is not crossing the blood-brain barrier, BBB). Currently there is thus, increasing interest in developing novel inhibitors of this protein. We have conducted pioneering research in the area and designed the first synthetic class of Hsp90 inhibitors, the purine-scaffold class (PU-class). We have also designed and developed several assays that probe biochemical and cellular inhibition of Hsp90. One such assay is proposed here for use in MLSCN. Discovery of novel Hsp90 inhibitors based on diverse chemical skeletons is necessary to fully harvest the therapeutic potential of the chaperone, and we propose here that such diversity may be obtained by screening large libraries of compounds against this target.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
antineoplastic, bioassay, diagnosis design /evaluation, drug discovery /isolation, fluorescence polarization, heat shock protein, molecular chaperone, neuropharmacologic agent, proteomics
antibiotic, chemical registry /resource, combinatorial chemistry, inhibitor /antagonist, neoplasm /cancer chemotherapy, peptide library
biotechnology
Institution: SLOAN-KETTERING INSTITUTE FOR CANCER RES 1275 YORK AVE NEW YORK, NY 10065 Fiscal Year: 2005 Department: Project Start: 15-SEP-2005 Project End: 30-SEP-2007 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZMH1