苯并三唑硫醇类衍生物的开发作为 DCN1-UBC12 相互作用的高活性抑制剂。
Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction.
机构信息
State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China; Department of Pathology, Oslo University Hospital, Faculty of Medicine, University of Oslo, Oslo, 0379, Norway.
State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Co-innovation Center of Henan Province for New Drug R & D and Preclinical Safety, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan, 450001, PR China.
出版信息
Eur J Med Chem. 2021 May 5;217:113326. doi: 10.1016/j.ejmech.2021.113326. Epub 2021 Mar 12.
Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.
DCN1 缺陷是一种重要的 Cullin 泛素化 1（DCN1）共 E3 连接酶。DCN1 的失调与各种癌症的发展高度相关。在此，从最初的高通量筛选中，发现了一种含有苯并三唑硫醇核心的新型命中化合物 5a（DCN1-UBC12 相互作用的 IC 值为 0.95μM）。进一步基于结构的优化导致 SK-464（IC 值为 26 nM）的发展。我们发现 SK-464 不仅在体外直接与 DCN1 结合，还与细胞内的 DCN1 结合，抑制 Cullin3 的泛素化，并阻碍两个 DCN1 过表达的鳞状癌细胞系（KYSE70 和 H2170）的迁移和侵袭。这些发现表明 SK-464 可能是一种针对 DCN1-UBC12 相互作用的新型先导化合物。
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