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Pustelny, K.* ; Grygier, P.* ; Barzowska, A.* ; Pucelik, B.* ; Matsuda, A.* ; Mrowiec, K.* ; Slugocka, E.* ; Popowicz, G.M. ; Dubin, G.* ; Czarna, A.*

Binding mechanism and biological effects of flavone DYRK1A inhibitors for the design of new antidiabetics.

Sci. Rep. 13:18114 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The selective inhibition of kinases from the diabetic kinome is known to promote the regeneration of beta cells and provide an opportunity for the curative treatment of diabetes. The effect can be achieved by carefully tailoring the selectivity of inhibitor toward a particular kinase, especially DYRK1A, previously associated with Down syndrome and Alzheimer's disease. Recently DYRK1A inhibition has been shown to promote both insulin secretion and beta cells proliferation. Here, we show that commonly available flavones are effective inhibitors of DYRK1A. The observed biochemical activity of flavone compounds is confirmed by crystal structures solved at 2.06 Å and 2.32 Å resolution, deciphering the way inhibitors bind in the ATP-binding pocket of the kinase, which is driven by the arrangement of hydroxyl moieties. We also demonstrate antidiabetic properties of these biomolecules and prove that they could be further improved by therapy combined with TGF-β inhibitors. Our data will allow future structure-based optimization of the presented scaffolds toward potent, bioavailable and selective anti-diabetic drugs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Beta-cell Proliferation; Alzheimers-disease; Rutin Improves; Molecular Docking; Oxidative Stress; Protein-kinase; Quercetin; Gossypin; Model; Activation
ISSN (print) / ISBN 2045-2322
e-ISSN 2045-2322
Zeitschrift Scientific Reports
Quellenangaben Band: 13, Heft: 1, Seiten: , Artikelnummer: 18114 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
Förderungen Priority Research Area BioS under the program 'Initiative of Excellence-Research University' at the Jagiellonian University in Krakow
DESY (Hamburg, Germany)
(Foundation for Polish Science)
TEAM
National Science Centre
This work was supported by a grant from the National Science Centre (UMO-2019/34/E/NZ1/00467) and by NAWA Polish Returns 2018 (PPN/PPO/2018/1/00046/U/00001) to A.C. We acknowledge the MCB Structural Biology Core Facility (supported by the TEAM TECH CORE F