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

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 DYR...

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Published in:Scientific reports 2023-10, Vol.13 (1), p.18114-18114, Article 18114
Main Authors: Pustelny, Katarzyna, Grygier, Przemyslaw, Barzowska, Agata, Pucelik, Barbara, Matsuda, Alex, Mrowiec, Krzysztof, Slugocka, Emilia, Popowicz, Grzegorz M., Dubin, Grzegorz, Czarna, Anna
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creator Pustelny, Katarzyna
Grygier, Przemyslaw
Barzowska, Agata
Pucelik, Barbara
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Mrowiec, Krzysztof
Slugocka, Emilia
Popowicz, Grzegorz M.
Dubin, Grzegorz
Czarna, Anna
description 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.
doi_str_mv 10.1038/s41598-023-44810-3
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subjects 631/154
631/45
631/535
692/4017
692/699
Alzheimer's disease
Antidiabetics
Beta cells
Biological effects
Cell proliferation
Diabetes
Diabetes mellitus
Down's syndrome
Flavones
Humanities and Social Sciences
Inhibitors
Insulin secretion
multidisciplinary
Neurodegenerative diseases
Science
Science (multidisciplinary)
Transforming growth factor-b
title Binding mechanism and biological effects of flavone DYRK1A inhibitors for the design of new antidiabetics
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