Publication： Journal of Enzyme Inhibition and Medicinal Chemistry

Date of Publication: 12 April 2022

Authors： Seo-Jung Han, Jae Eun Jung, Do Hee Oh, Minsup Kim, Jae-Min Kim, Kyung-Sook Chung, Hee-Soo Han, Jeong-Hun Lee, Kyung-Tae Lee, Hee Jin Jeong, In Ho Park, Eunkyeong Jeon, Jeon-Soo Shin, Dongkeun Hwang, Art E. Cho, Duck-Hyung Lee & Taebo Sim

doi: https://doi.org/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 7a potently inhibited Lck kinase with great selectivity (IC50 of 23.0 nM). It was found that 7a and its derivatives possessed high selectivity for Lck over even structurally conserved all Src family kinases. We also observed that 7a inhibited Lck activation in Jurkat T cells. Moreover, 7a 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.