Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
Division of Bio-Medical Science & Technology, KIST School, UST, Seoul, Republic of Korea.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):1257-1277. doi: 10.1080/14756366.2022.2068148.
Identification of highly selective type II kinase inhibitors is described. Two different chiral peptidomimetic scaffolds were introduced on the tail region of non-selective type II kinase inhibitor GNF-7 to enhance the selectivity. Kinome-wide selectivity profiling analysis showed that type II kinase inhibitor potently inhibited Lck kinase with great selectivity (IC of 23.0 nM). It was found that and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that inhibited Lck activation in Jurkat T cells. Moreover, was found to alleviate clinical symptoms in DSS-induced colitis mice. This study provides a novel insight into the design of selective type II kinase inhibitors by adopting chiral peptidomimetic moieties on the tail region.
本文描述了高选择性 II 型激酶抑制剂的鉴定。在非选择性 II 型激酶抑制剂 GNF-7 的尾部引入了两种不同的手性肽模拟物支架，以提高选择性。激酶组广泛的选择性分析表明，II 型激酶抑制剂 强烈抑制 Lck 激酶，具有很好的选择性（IC 为 23.0 nM）。研究发现， 及其衍生物对 Lck 的选择性很高，甚至超过结构保守的所有 Src 家族激酶。我们还观察到 抑制 Jurkat T 细胞中 Lck 的激活。此外，发现 在 DSS 诱导的结肠炎小鼠中能减轻临床症状。本研究通过在手性肽模拟物尾部引入手性肽模拟物，为设计选择性 II 型激酶抑制剂提供了新的思路。
