Optimization of biaryl Selective HDAC1&2 Inhibitors (SHI-1:2)

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• 作者：David J. Witter ; Paul Harrington ; Kevin J. Wilson ; Melissa Chenard ; Judith C. Fleming ; Brian Haines ; Astrid M. Kral ; J. Paul Secrist ; Thomas A. Miller
• 关键词：Histone deacetylase ; HDAC ; Aminobenzamides ; Biaryl
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 January 2008
• 年：2008
• 卷：18
• 期：2
• 页码：726-731
• 全文大小：152 K

文摘

A class of biaryl benzamides was identified and optimized as selective HDAC1&2 inhibitors (SHI-1:2). These agents exhibit selectivity over class II HDACs 4–7, as well as class I HDACs 3 and 8; providing examples of selective HDAC inhibitors for the HDAC isoforms most closely associated with cancer. The hypothesis for the increased selectivity is the binding of a pendant aromatic group in the internal cavity of the HDAC1&2 enzymes. SAR development based on an initial lead led to a series of potent and selective inhibitors with reduced off-target activity and tumor growth inhibition activity in a HCT-116 xenograft model.