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1. Synthesis, biological evaluation and binding mode of new CLK1/DYRK1A inhibitors presenting a pyrido[3,4-g]quinazoline moiety

Author

TAZARKI, H., Zeinyeh, W., ESVAN, Y. J., Knapp, S., Chatterjee, D., Schröder, M., JOERGER, A. C., Khiari, J., JOSSELIN, B., Baratte, B., Bach, S., Ruchaud, S., ANIZON, F., Giraud, F., Moreau, P., Institut de Chimie de Clermont-Ferrand (ICCF), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), and Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA)

Subjects
[CHIM]Chemical Sciences, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2021

2. New pyrido[3,4-g]quinazoline derivatives as CLK1 and DYRK1A inhibitors: synthesis, biological evaluation and binding mode analysis.

Author

Tazarki H, Zeinyeh W, Esvan YJ, Knapp S, Chatterjee D, Schröder M, Joerger AC, Khiari J, Josselin B, Baratte B, Bach S, Ruchaud S, Anizon F, Giraud F, and Moreau P

Subjects
Cell Line, Tumor, Chemistry Techniques, Synthetic, Humans, Molecular Docking Simulation, Protein Binding, Protein Conformation, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors metabolism, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases chemistry, Protein-Tyrosine Kinases chemistry, Quinazolines chemistry, Quinazolines metabolism, Structure-Activity Relationship, Dyrk Kinases, Drug Design, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases metabolism, Quinazolines chemical synthesis, Quinazolines pharmacology
Abstract

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., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Published
2019
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