Hsp90 molecular chaperone inhibitors Are we there yet外文文献资料.PDF.docxVIP

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2019-03-27 发布于河北
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Hsp90 molecular chaperone inhibitors Are we there yet外文文献资料.PDF.docx

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Neckers and Workman Page Neckers and Workman Page PAGE \* MERGEFORMAT # Clin Cancer Res. Clin Cancer Res. Author manuscript; available in PMC 2012 July 1 ? Published in final edited form as:Clin Cancel Res. 2012 January 1; 18(1): 64—76. doi:10.1158/1078-0432.CCR- Published in final edited form as: Clin Cancel Res. 2012 January 1; 18(1): 64—76. doi:10.1158/1078-0432.CCR- -1000. NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-bA Author ManuscriptHsp90 molecular chaperone inhibitors: Are we there yet? NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-bA Author Manuscript Len Neckers1 and Paul Workman2 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike Bldg. 10/CRC, Room 1-5940, Bethesda，MD 20892-1107 USA Signal Transduction and Molecular Pharmacology Team，Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories，15 Cotswold Road, Sutton SM2 5NG UK Abstract Heat shock protein (Hsp) 90 is an ATP-dependent molecular chaperone exploited by malignant cells to support activated oncoproteins，including many cancer-associated kinases and transcription factors，and is essential for oncogenic transformation. Originally viewed with skepticism, Hsp90 inhibitors are now actively pursued by the pharmaceutical industry, with 17 agents having entered clinical trials. Hsp90’s druggability was established using the natural products geldanamycin and radicicol which mimic the unusual ATP structure adopted in the chaperone’s N-terminal nucleotide-binding pocket and cause potent and selective blockade of ATP binding/hydrolysis，inhibit chaperone function，deplete oncogenic clients，and demonstrate antitumor activity. Preclinical data with these natural products have heightened interest in Hsp90 as a drug target，and 17-allylamino-17-demethoxygeldanamycin (17-AAG，tanespimycin) has demonstrated clinical activity (as defined by RECIST criteria) in HER2+ breast cancer.