Structure-Guided Discovery of Potent and Selective DYRK1A Inhibitors

The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided opt...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 64; no. 10; pp. 6745 - 6764
Main Authors:	Weber, Csaba, Sipos, Melinda, Paczal, Attila, Balint, Balazs, Kun, Vilibald, Foloppe, Nicolas, Dokurno, Pawel, Massey, Andrew J, Walmsley, David Lee, Hubbard, Roderick E, Murray, James, Benwell, Karen, Edmonds, Thomas, Demarles, Didier, Bruno, Alain, Burbridge, Mike, Cruzalegui, Francisco, Kotschy, Andras
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 27-05-2021
Subjects:	Adenosine Triphosphate - chemistry Animals Binding Sites Cell Line, Tumor Cell Survival - drug effects Cyclin-Dependent Kinase 9 - antagonists & inhibitors Cyclin-Dependent Kinase 9 - metabolism Drug Design Drug Evaluation, Preclinical Dyrk Kinases Female Humans Mice Mice, Nude Molecular Docking Simulation Ovarian Neoplasms - drug therapy Ovarian Neoplasms - pathology Phosphorylation - drug effects Protein Isoforms - antagonists & inhibitors Protein Isoforms - metabolism Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - metabolism Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - metabolism Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - metabolism Pyrimidines - chemistry Pyrimidines - metabolism Pyrimidines - pharmacology Pyrimidines - therapeutic use Structure-Activity Relationship
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Summary:	The kinase DYRK1A is an attractive target for drug discovery programs due to its implication in multiple diseases. Through a fragment screen, we identified a simple biaryl compound that is bound to the DYRK1A ATP site with very high efficiency, although with limited selectivity. Structure-guided optimization cycles enabled us to convert this fragment hit into potent and selective DYRK1A inhibitors. Exploiting the structural differences in DYRK1A and its close homologue DYRK2, we were able to fine-tune the selectivity of our inhibitors. Our best compounds potently inhibited DYRK1A in the cell culture and in vivo and demonstrated drug-like properties. The inhibition of DYRK1A in vivo translated into dose-dependent tumor growth inhibition in a model of ovarian carcinoma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.1c00023