Sun Qi-Zheng, Lin Gui-Feng, Li Lin-Li, Jin Xi-Ting, Huang Lu-Yi, Zhang Guo, Yang Wei, Chen Kai, Xiang Rong, Chen Chong, Wei Yu-Quan, Lu Guang-Wen, Yang Sheng-Yong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy , Chengdu 610041, P.R. China.
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University , Sichuan 610041, P.R. China.
J Med Chem. 2017 Jul 27;60(14):6337-6352. doi: 10.1021/acs.jmedchem.7b00665. Epub 2017 Jul 17.
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.
自噬诱导剂是治疗多种疾病的新的有前景的药物。然而，缺乏用于临床应用的安全自噬诱导剂。最近发现抑制细胞分裂周期蛋白2样激酶1（CLK1）可有效诱导自噬。不幸的是，大多数已知的CLK1抑制剂的选择性都不尽人意。在此，我们报告了一系列含有1H-[1,2,3]三唑并[4,5-c]喹啉支架的新型CLK1抑制剂的发现。其中，化合物25是最有效和最具选择性的，对CLK1的IC值为2 nM。解析了CLK1与化合物25复合的晶体结构，并解释了化合物25的效力和激酶选择性。化合物25能够在体外试验中诱导自噬，并在对乙酰氨基酚（APAP）诱导的肝损伤小鼠模型中显示出显著的肝保护作用。总体而言，由于其效力和选择性，化合物25可在未来的作用机制或自噬相关疾病治疗研究中用作化学探针或药物。
