Design, synthesis, and evaluation of small molecule Hsp90 probes Journal Article


Authors: Taldone, T.; Zatorska, D.; Patel, P. D.; Zong, H.; Rodina, A.; Ahn, J. H.; Moulick, K.; Guzman, M. L.; Chiosis, G.
Article Title: Design, synthesis, and evaluation of small molecule Hsp90 probes
Abstract: A number of compounds from different chemical classes are known to bind competitively to the ATP-pocket of Hsp90 and inhibit its chaperone function. The natural product geldanamycin was the first reported inhibitor of Hsp90 and since then synthetic inhibitors from purine, isoxazole and indazol-4-one chemical classes have been discovered and are currently or soon to be in clinical trials for the treatment of cancer. In spite of a similar binding mode to Hsp90, distinct biological profiles were demonstrated among these molecules, both in vitro and in vivo. To better understand the molecular basis for these dissimilarities, we report here the synthesis of chemical tools for three Hsp90 inhibitor classes. These agents will be useful for probing tumor-by-tumor the Hsp90 complexes isolated by specific inhibitors. Such information will lead to better understanding of tumor specific molecular markers to aid in their clinical development. It will also help to elucidate the molecular basis for the biological differences observed among Hsp90 inhibitors. © 2011 Elsevier Ltd. All rights reserved.
Keywords: controlled study; unclassified drug; binding affinity; breast cancer; antineoplastic activity; cancer cell culture; drug design; drug synthesis; molecular marker; heat shock protein 90 inhibitor; heat shock protein 90; molecular docking; molecular probe; binding competition; leukemia cell line; 5 (2,4 dihydroxy 5 isopropylphenyl) 4 (4 morpholinomethylphenyl) 3 isoxazolecarboxylic acid ethylamide; snx 2112; isoxazole derivative; pu h 71; docking; nvp-auy922; pu-h71; snx-2112; indazol 4 one derivative; enzyme inhibitor complex
Journal Title: Bioorganic & Medicinal Chemistry
Volume: 19
Issue: 8
ISSN: 0968-0896
Publisher: Pergamon-Elsevier Science Ltd  
Date Published: 2011-04-15
Start Page: 2603
End Page: 2614
Language: English
DOI: 10.1016/j.bmc.2011.03.013
PROVIDER: scopus
PMCID: PMC3143825
PUBMED: 21459002
DOI/URL:
Notes: --- - "Export Date: 23 June 2011" - "CODEN: BMECE" - "Source: Scopus"
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MSK Authors
  1. Kamalika Moulick
    16 Moulick
  2. Gabriela Chiosis
    253 Chiosis
  3. Tony Taldone
    92 Taldone
  4. James H Ahn
    10 Ahn
  5. Pallav D Patel
    15 Patel