Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 166, Issue -, Pages 304-317Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.01.052
Keywords
Pyridoquinazolines; Kinase inhibitors; CLK1; DYRKIA
Categories
Funding
- Auvergne Region (Jeune Chercheur Program)
- French Ministry of Higher Education and Research
- Carthage University (Tunisia)
- Biogeneouest/Region Bretagne, Canceropole Grand Ouest
- GIS IBiSA
- German Research Foundation [JO 1473/1-1]
- SGC [1097737]
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation
- Eshelman Institute
- Genome Canada through Ontario Genomics Institute, Innovative Medicines Initiative (EU/EFPIA) [115766]
- Janssen
- Merck Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome Trust
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Cdc2-like kinase 1 (CLK1) and dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) are involved in the regulation of alternative pre-mRNA splicing. Dysregulation of this process has been linked to cancer progression and neurodegenerative diseases, making CLK1 and DYRK1A important therapeutic targets. Here we describe the synthesis of new pyrido[3,4-g]quinazoline derivatives and the evaluation of the inhibitory potencies of these compounds toward CDK5, CK1, GSK3, CLK1 and DYRK1A. Introduction of aminoalkylamino groups at the 2-position resulted in several compounds with low nanomolar affinity and selective inhibition of CLK1 and/or DYRK1A. Their evaluation on several immortalized or cancerous cell lines showed varying degree of cell viability reduction. Co-crystal structures of CLK1 with two of the most potent compounds revealed two alternative binding modes of the pyrido[3,4-g]quinazoline scaffold that can be exploited for future inhibitor design. (C) 2019 Elsevier Masson SAS. All rights reserved.
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