N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies
N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies
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N-苄基哌啶醇衍生物作为新型 USP7 抑制剂：结构-活性关系和 X 射线晶体学研究
DOI：
10.1016/j.ejmech.2020.112279
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发表时间：
2020-08-01
影响因子：
6.7
通讯作者：
Wen, Xiaoan
中科院分区：
文献类型：
--
作者：
Li, Minglei;Liu, Shengjie;Wen, Xiaoan
USP 7作为一种去泛素化酶，在调节包括MDM 2和DNMT 1在内的一些癌蛋白的稳定性方面发挥重要作用，因此代表了潜在的抗癌靶标。通过对USP 7与已报道的哌啶醇类抑制剂复合物的共晶结构的比较分析，我们注意到USP 7的Phe 409亚位点可能对配体具有良好的适应性。在此基础上，设计、合成了55个N-芳香族和N-苄基哌啶醇衍生物，并进行了生物活性评价，其中化合物L55被鉴定为具有高度选择性和有效的USP 7抑制剂（IC 50 = 40.8 nM，K-D = 78.3 nM）。X射线晶体学研究表明，L55与USP 7结合的新姿势与以前报道的抑制剂非常不同。细胞实验结果表明，L55对LNCaP（IC 50 = 29.6 nM）和RS 4; 11（IC 50 = 41.6 nM）细胞具有较强的抗肿瘤活性，其作用机制可能是通过诱导细胞死亡和限制G 0/G1期及S期而实现的。此外，L55剂量依赖性地降低MDM 2和DNMT 1的蛋白水平，并增加p53和p21的蛋白水平。这些发现可能对设计USP 7抑制剂的新结构类别具有重要意义。(C)2020 Elsevier Masson SAS。All rights reserved.
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.