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Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer
Authors:Leah K Forsberg  Weiya Liu  Jeffrey Holzbeierlein  Brian SJ Blagg
Institution:1. Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott 4070, The University of Kansas, Lawrence, Kansas 66045-7563, United States;2. Department of Urology, 3901 Rainbow Boulevard, Stop 3016, The University of Kansas Medical Center, Kansas City, Kansas 66160, United States
Abstract:Heat Shock Protein 90 (Hsp90) is a molecular chaperone under clinical investigation for the treatment of neurodegenerative diseases and cancer. Neuroprotective Hsp90 C-terminal inhibitors (novologues) contain a biaryl ring system, and include KU-596, which was modified and investigated for potential anti-cancer activity. Incorporation of a benzamide group onto the biaryl novologues in lieu of the acetamide yielded compounds that manifest anti-cancer activity. Further exploration of the central phenyl ring led to compounds with enhanced anti-proliferative activity. The design, synthesis, and evaluation of these new analogs against breast and prostate cancer cell lines is reported herein, where it was found that 8b and 10 manifest potent anti-proliferative activity and a robust degradation of Hsp90 client-dependent proteins.
Keywords:Breast cancer  Prostate cancer  Heat Shock Protein 90  Hsp90 inhibitors  Novobiocin analogs
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