Design, synthesis, and biological evaluation of benzodiazepine-based SUMO-specific protease 1 inhibitors

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• 作者：Zhitao  ; Qiao^a ;   ; ^&dagger ; ; Weiwei  ; Wang^b ;   ; ^&dagger ; ; Lie  ; Wang^a ; Donghua  ; Wen^b ; Yaxue  ; Zhao^a ; Qing  ; Wang^a ; Qingqing  ; Meng^a ; Guoqiang  ; Chen^b ; Yingli  ; Wu^b ;   ; ^{wuyingli@shsmu.edu.cn} ; Huchen  ; Zhou^a ;   ; ^{hczhou@sjtu.edu.cn}
• 关键词：Drug discovery ; Inhibitor ; Structure&ndash ; activity relationship ; Benzodiazepine ; Peptidomimetics
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2011
• 出版时间：1 November 2011
• 年：2011
• 卷：21
• 期：21
• 页码：6389-6392
• 全文大小：497 K

文摘

As the best-characterized ubiquitin-like protein (UBL), small ubiquitin-related modifier (SUMO) was found to conjugate with a number of proteins to regulate cellular functions including transcription, signal transduction, and cell cycle. While E1, E2 and E3 ligases are responsible for the forward SUMOylation reaction, SUMO-specific proteases (SENPs) reversibly remove SUMO from the SUMOylated proteins. Recently, SENP1 was found to be a potential therapeutic target for the treatment of prostate cancers, but the design and synthesis of its inhibitors have not been reported. We designed and synthesized a series of benzodiazepine-based SENP1 inhibitors, and they showed inhibitory activity as good as IC₅₀ = 9.2 ¦ÌM (compound 38). The structure¨Cactivity relationship was also discussed.