2. Academic Validation
  3. Rational design and appraisal of selective Cdc2-Like kinase 1 (Clk1) inhibitors as novel autophagy inducers for the treatment of acute liver injury (ALI)

Rational design and appraisal of selective Cdc2-Like kinase 1 (Clk1) inhibitors as novel autophagy inducers for the treatment of acute liver injury (ALI)

  • Eur J Med Chem. 2023 Mar 15;250:115168. doi: 10.1016/j.ejmech.2023.115168.
Tao Yang 1,  Yingxue Yang 2,  Yong Chen 2,  Minghai Tang 2,  Mingsong Shi 2,  Yang Tian 3,  Xue Yuan 2,  Zhuang Yang 4,  Lijuan Chen 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China.
  • 3 Department of Otolaryngology Head and Neck Surgery, The Third People's Hospital of Chengdu, Chengdu, 610014, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China; Chengdu Zenitar Biomedical Technology Co., Ltd, Chengdu, 610041, China. Electronic address: [email protected].
  • 5 State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, China; Chengdu Zenitar Biomedical Technology Co., Ltd, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 36780830 DOI: 10.1016/j.ejmech.2023.115168
Abstract

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 IC50 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.

Figures
Products