Modified biphenyl Hsp90 C-terminal inhibitors for the treatment of cancer

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Forsberg, Leah K.¹  Liu, Weiya²  Holzbeierlein, Jeffrey²  Blagg, Brian S. J.¹ 

[1] Univ Kansas, Dept Med Chem, 1251 Wescoe Hall Dr,Malott 4070, Lawrence, KS 66045 USA

[2] Univ Kansas, Med Ctr, Dept Urol, 3901 Rainbow Blvd,Stop 3016, Kansas City, KS 66160 USA

关键词: Breast cancer;    Prostate cancer;    Heat Shock Protein 90;    Hsp90 inhibitors;    Novobiocin analogs;   

DOI  :  10.1016/j.bmcl.2017.07.030

来源: Elsevier

【 摘 要 】

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 anticancer 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. (C) 2017 Published by Elsevier Ltd.

【 授权许可】

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