期刊
MOLECULES
卷 24, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/molecules24224090
关键词
DYRK1A; indole; molecular docking; protein kinase inhibitor; solubility; nephelometry; X-ray structure analysis
资金
- Fonds Unique Interministeriel (FUI) TRIAD project
- Fondation Jerome Lejeune
- FP7-KBBE-2012 grant (BlueGenics)
- SGC [1097737]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) [ULTRA-DD] [115766]
- Janssen
- Merck KGaA, Germany
- MSD
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome [106169/ZZ14/Z]
- Collaborative Sonderforschungsbereich 1177 Autophagy [SFB1177]
- German Research Foundation (DFG) [Ku-1371/10-1]
- German Research Foundation
- Technische Universitat Braunschweig
Since hyperactivity of the protein kinase DYRK1A is linked to several neurodegenerative disorders, DYRK1A inhibitors have been suggested as potential therapeutics for Down syndrome and Alzheimer's disease. Most published inhibitors to date suffer from low selectivity against related kinases or from unfavorable physicochemical properties. In order to identify DYRK1A inhibitors with improved properties, a series of new chemicals based on [b]-annulated halogenated indoles were designed, synthesized, and evaluated for biological activity. Analysis of crystal structures revealed a typical type-I binding mode of the new inhibitor 4-chlorocyclohepta[b]indol-10(5H)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.
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