选择性小分子抑制剂的USP7抑制的分子基础
Andrew P Turnbull1, Stephanos Ioannidis2, Wojciech W Krajewski1
1CRUK Therapeutic Discovery Laboratories, London Bioscience Innovation Centre, London NW1 0NH, UK.
Nature
|October 19, 2017
概括
两种新的化合物FT671和FT827有效地抑制了泛素特异蛋白酶7 (USP7). 这种抑制会破坏促进癌症的蛋白质,重新激活p53等瘤抑制剂,并减缓瘤的生长.
科学领域:
- 生物化学
- 分子生物学
- 癌症学
背景情况:
- 蛋白质无化调节细胞蛋白质的稳定性,并且其失调与癌症有关.
- 脱基因酶 (DUBs) 通过降解特定的蛋白质,包括以前被认为是"无药"的蛋白质,去除无素,提供治疗点.
- 在癌症中,抑制泛素特异性蛋白酶7 (USP7) 会降解致癌性E3连接酶MDM2,从而重新激活瘤抑制剂p53.
研究的目的:
- 确定和描述USP7的新型抑制剂.
- 阐明新化合物抑制USP7的机制.
- 在临床前癌症模型中评估USP7抑制的治疗潜力.
主要方法:
- 在体外和细胞测定以评估USP7抑制和特异性.
- 与抑制剂复合的USP7的同晶结构分析.
- 分析USP7基质和p53的蛋白质含量.
- 对p53目标基因转录和p21诱导的分析.
- 评估小鼠瘤生长抑制的体内研究.
主要成果:
- 在体外和人体细胞中,FT671和FT827具有高亲和力和特异性抑制USP7.
- 同晶体结构揭示了USP7的动态口袋中的新型结合相互作用.
- 治疗FT671导致MDM2不稳定,增加p53水平和p53向基因激活,包括p21.
- 在接受FT671治疗的小鼠中显著抑制瘤生长.
结论:
- FT671和FT827是具有独特结合方式的强效USP7抑制剂.
- 抑制USP7有效地重新激活p53瘤抑制途径.
- 抑制USP7是一种有前途的治疗策略,用于治疗USP7依赖的癌症.
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