Key Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, Frontiers Center for Materiobiology and Dynamic Chemistry, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, People's Republic of China, China.
Zhejiang Hisun Pharmaceutical Co, Ltd, Taizhou, 318099 Zhejiang, China.
Biomed Res Int. 2022 May 9;2022:6383893. doi: 10.1155/2022/6383893. eCollection 2022.
Due to the high homology of the ATP sites of the JAK family, the development of selective inhibitors for a certain JAK isoform is extremely challenging. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Based on the clinical compound BMS-986165, through structure-activity relationship studies, a class of acyl compounds with excellent TYK2 inhibitory activity and selectivity to other subtypes of the JAK family was discovered.
由于 JAK 家族的 ATP 结合位点具有高度同源性，因此开发针对特定 JAK 同工型的选择性抑制剂极具挑战性。我们实现 TYK2 高选择性的策略依赖于靶向 TYK2 假激酶（JH2）结构域。以临床化合物 BMS-986165 为基础，通过构效关系研究，发现了一类具有优异 TYK2 抑制活性和对 JAK 家族其他亚型选择性的酰基化合物。
