State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
State Key Laboratory of Microbial Metabolism, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
Eur J Med Chem. 2020 Oct 15;204:112553. doi: 10.1016/j.ejmech.2020.112553. Epub 2020 Jul 19.
The SUMO (small ubiquitin-related modifier)-specific proteases (SENPs) are responsible for the cleavage of SUMO from its target proteins, thus play important roles in the dynamic SUMOylation and deSUMOylation processes. SENPs are related to a variety of human diseases including cancer and represent a new class of potential therapeutic targets with mechanism of action that is likely to be different from that of current clinically used drugs. However, potent inhibitors that are selective within the SENPs family members still remain a challenge due to their high homology. In order to demonstrate the feasibility of developing selective inhibitors within the SENPs family, we chose SENP1/2/5 as representatives, aiming to identify inhibitors with selectivity among the members. Starting from a hit compound ZCL951 from virtual screening, a series of benzothiophene-2-carboxamide inhibitors were designed based on the protein structures of SENP1, 2, and 5. First, an unoccupied hydrophobic pocket was first identified which led to IC as low as 0.56 μM. Furthermore, the ethylacetate 77 gave both submicromolar inhibitory activity and 33-fold selectivity for SENP2 versus SENP5. They are the most potent and selective nonpeptidic inhibitor reported so far for the SENPs family, as far as we are aware. Their structure-activity relationship was also discussed.
SUMO（小泛素相关修饰物）特异性蛋白酶（SENPs）负责从其靶蛋白中切割 SUMO，因此在 SUMO 化和去 SUMO 化的动态过程中发挥重要作用。SENPs 与多种人类疾病有关，包括癌症，代表了一类新的潜在治疗靶点，其作用机制可能与当前临床使用的药物不同。然而，由于它们的高度同源性，仍然难以获得针对 SENPs 家族成员的有效抑制剂。为了证明在 SENPs 家族内开发选择性抑制剂的可行性，我们选择 SENP1/2/5 作为代表，旨在鉴定成员之间具有选择性的抑制剂。从虚拟筛选的命中化合物 ZCL951 出发，根据 SENP1、2 和 5 的蛋白质结构设计了一系列苯并噻吩-2-甲酰胺抑制剂。首先，首次鉴定了一个未占据的疏水性口袋，导致 IC50 低至 0.56 μM。此外，乙酯 77 对 SENP2 与 SENP5 的抑制活性分别为亚微摩尔和 33 倍，选择性最高。据我们所知，它们是迄今为止报道的针对 SENPs 家族最有效和选择性的非肽抑制剂。还讨论了它们的构效关系。
