5X8I

Crystal structure of human CLK1 in complex with compound 25

5X8I の概要

• エントリーDOI: 10.2210/pdb5x8i/pdb
• 分子名称: Dual specificity protein kinase CLK1, 5-[1-[(1S)-1-(4-fluorophenyl)ethyl]-[1,2,3]triazolo[4,5-c]quinolin-8-yl]-1,3-benzoxazole (3 entities in total)
• 機能のキーワード: inhibitor, complex, kinase, clk1, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Nucleus: P49759
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 81949.97

構造登録者

Sun, Q.Z.,Lin, G.F.,Li, L.L.,Jin, X.T.,Huang, L.Y.,Zhang, G.,Wei, Y.Q.,Lu, G.W.,Yang, S.Y. (登録日: 2017-03-02, 公開日: 2017-08-16, 最終更新日: 2023-11-22)

主引用文献

Sun, Q.Z.,Lin, G.F.,Li, L.L.,Jin, X.T.,Huang, L.Y.,Zhang, G.,Yang, W.,Chen, K.,Xiang, R.,Chen, C.,Wei, Y.Q.,Lu, G.W.,Yang, S.Y.
Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers
J. Med. Chem., 60:6337-6352, 2017

PubMed Abstract: Autophagy inducers represent new promising agents for the treatment of a wide range of medical illnesses. However, safe autophagy inducers for clinical applications are lacking. Inhibition of cdc2-like kinase 1 (CLK1) was recently found to efficiently induce autophagy. Unfortunately, most of the known CLK1 inhibitors have unsatisfactory selectivity. Herein, we report the discovery of a series of new CLK1 inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold. Among them, compound 25 was the most potent and selective, with an IC value of 2 nM against CLK1. The crystal structure of CLK1 complexed with compound 25 was solved, and the potency and kinase selectivity of compound 25 were interpreted. Compound 25 was able to induce autophagy in in vitro assays and displayed significant hepatoprotective effects in the acetaminophen (APAP)-induced liver injury mouse model. Collectively, due to its potency and selectivity, compound 25 could be used as a chemical probe or agent in future mechanism-of-action or autophagy-related disease therapy studies.

PubMed: 28692292
DOI: 10.1021/acs.jmedchem.7b00665

実験手法

X-RAY DIFFRACTION (1.902 Å)