Yang Tao, Yang Yingxue, Chen Yong, Tang Minghai, Shi Mingsong, Tian Yang, Yuan Xue, Yang Zhuang, Chen Lijuan
State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.
State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.
Eur J Med Chem. 2023 Mar 15;250:115168. doi: 10.1016/j.ejmech.2023.115168. Epub 2023 Feb 7.
Autophagy inducers are promising agents for treating certain medical illnesses, while no safe autophagy inducers are in clinical applications. Cdc2-like kinase 1 (Clk1) inhibitors induce autophagy efficiently; however, most Clk1 inhibitors lack selectivity, especially against Dyrk1A kinase. Herein, we report a series of 1H-pyrrolo[2,3-b]pyridin-5-amine derivatives as novel Clk1 inhibitors. Through detailed structural modification and structure-activity relationship studies, compound 10ad shows potent and selective inhibition for Clk1, with an IC value of 5 nM and over 300-fold selectivity for Dyrk1A. Related kinase screening also validates the selectivity of compound 10ad. Furthermore, compound 10ad potently induces autophagy in vitro and exhibits significant hepatoprotective effects in the acute liver injury model induced by acetaminophen (paracetamol). In general, due to the excellent potency and selectivity, compound 10ad was worth further investigation in the treatment of autophagy-related diseases.
自噬诱导剂是治疗某些疾病的有前景的药物，但目前尚无安全的自噬诱导剂应用于临床。Cdc2样激酶1（Clk1）抑制剂能有效诱导自噬；然而，大多数Clk1抑制剂缺乏选择性，尤其是对双重特异性酪氨酸磷酸化调节激酶1A（Dyrk1A）激酶。在此，我们报道了一系列新型的1H-吡咯并[2,3-b]吡啶-5-胺衍生物作为Clk1抑制剂。通过详细的结构修饰和构效关系研究，化合物10ad对Clk1表现出强效且选择性的抑制作用，其IC值为5 nM，对Dyrk1A的选择性超过300倍。相关激酶筛选也验证了化合物10ad的选择性。此外，化合物10ad在体外能有效诱导自噬，并在对乙酰氨基酚（扑热息痛）诱导的急性肝损伤模型中表现出显著的肝保护作用。总体而言，由于其优异的活性和选择性，化合物10ad在自噬相关疾病的治疗中值得进一步研究。
