6T6A

Crystal structure of DYRK1A complexed with KuFal319 (compound 11)

Summary for 6T6A

• Entry DOI: 10.2210/pdb6t6a/pdb
• Descriptor: Dual specificity tyrosine-phosphorylation-regulated kinase 1A, TETRAETHYLENE GLYCOL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: dyrk1a, splicing kinase, kinase inhibitor, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 171235.08

Authors

Chaikuad, A.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Kunick, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2019-10-18, release date: 2019-12-04, Last modification date: 2024-11-13)

Primary citation

Lechner, C.,Flasshoff, M.,Falke, H.,Preu, L.,Loaec, N.,Meijer, L.,Knapp, S.,Chaikuad, A.,Kunick, C.
[ b ]-Annulated Halogen-Substituted Indoles as Potential DYRK1A Inhibitors.
Molecules, 24:-, 2019

PubMed Abstract: 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 []-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[]indol-10(5)-one in DYRK1A, exploiting mainly shape complementarity for tight binding. Conversion of the DYRK1A inhibitor 8-chloro-1,2,3,9-tetrahydro-4-carbazol-4-one into a corresponding Mannich base hydrochloride improved the aqueous solubility but abrogated kinase inhibitory activity.

PubMed: 31766108
DOI: 10.3390/molecules24224090

Experimental method

X-RAY DIFFRACTION (2.8 Å)