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Discovery of Potent and Selective Inhibitors of Cdc2-Like Kinase 1 (CLK1) as a New Class of Autophagy Inducers.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2017 Jul 27; Vol. 60 (14), pp. 6337-6352. Date of Electronic Publication: 2017 Jul 17. - Publication Year :
- 2017
-
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 <subscript>50</subscript> 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.
- Subjects :
- Acetaminophen
Animals
Cell Line
Chemical and Drug Induced Liver Injury pathology
Humans
Liver drug effects
Liver pathology
Male
Mice
Mice, Inbred C57BL
Models, Molecular
Protective Agents chemical synthesis
Protective Agents pharmacology
Quinolines chemical synthesis
Quinolines pharmacology
Stereoisomerism
Structure-Activity Relationship
Triazoles chemical synthesis
Triazoles pharmacology
Autophagy drug effects
Chemical and Drug Induced Liver Injury drug therapy
Protective Agents chemistry
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein-Tyrosine Kinases antagonists & inhibitors
Quinolines chemistry
Triazoles chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 60
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28692292
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b00665