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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies
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N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies

机译：N-苄基哌啶酚衍生物作为新型USP7抑制剂：结构 - 活性关系和X射线晶体研究

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摘要

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC50 = 40.8 nM, K-D = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC50 = 29.6 nM) and RS4; 11 (IC50 = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：USP7作为氘素酶在调节包括MDM2和DNMT1的一些癌蛋白的稳定性方面起着重要作用，因此代表潜在的抗癌目标。通过对报告的哌啶酚抑制剂复合物中USP7共晶结构的比较分析，我们注意到USP7 PHE409子位点可能对配体具有良好的适应性。基于该观察结果，设计了55种N-芳族和N-苄基哌啶酚衍生物，合成和生物学评价，其中化合物L55被鉴定为高度选择性和有效的USP7抑制剂（IC50 = 40.8nm，K-D = 78.3nm）。 X射线晶体研究表明，L55与USP7结合，其具有与先前报道的抑制剂非常不同的新姿势。细胞测定结果表明，L55对LNCAP（IC50 = 29.6nm）和RS4具有强抗肿瘤活性; 11（IC50 = 41.6nm）细胞，可能通过诱导细胞死亡并限制G0 / G1和S阶段。此外，L55依赖性降低了MDM2和DNMT1的蛋白质水平，并增加了P53和P21的蛋白质水平。这些发现可能对设计新型结构类别的USP7抑制剂具有有价值的影响。 （c）2020 Elsevier Masson SAS。版权所有。

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  • 作者

    Li Minglei; Liu Shengjie; Chen Hui; Zhou Xinyu; Zhou Jin; Zhou Shuxi; Yuan Haoliang; Xu Qing-Long; Liu Jun; Cheng Keguang; Sun Hongbin; Wang Yue; Chen Caiping; Wen Xiaoan;

  • 作者单位

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    Guangxi Normal Univ State Key Lab Chem &

    Mol Engn Med Resources Sch Chem &

    Pharm Guilin 541004;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Sch Sci Nanjing 211198 Peoples R China;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

    China Pharmaceut Univ Jiangsu Key Lab Drug Discovery Metab Dis State Key Lab Nat Med Nanjing;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    USP7; Piperidine; Structure-activity relationship; Crystallographic study; Deubiquitinase;

    机译：USP7;哌啶;结构 - 活性关系;晶体研究;脱硫酶;

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