Identification of Novel GSK-3β Hits Using Competitive Biophysical Assays
Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer's disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D 19F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:23 |
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| Enthalten in: |
International journal of molecular sciences - 23(2022), 7 vom: 31. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Balboni, Beatrice [VerfasserIn] |
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| Links: |
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| Themen: |
8L70Q75FXE |
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| Anmerkungen: |
Date Completed 13.04.2022 Date Revised 15.04.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/ijms23073856 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM339388269 |
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| 520 | |a Glycogen synthase kinase 3 beta (GSK-3β) is an evolutionarily conserved serine-threonine kinase dysregulated in numerous pathologies, such as Alzheimer's disease and cancer. Even though GSK-3β is a validated pharmacological target most of its inhibitors have two main limitations: the lack of selectivity due to the high homology that characterizes the ATP binding site of most kinases, and the toxicity that emerges from GSK-3β complete inhibition which translates into the impairment of the plethora of pathways GSK-3β is involved in. Starting from a 1D 19F NMR fragment screening, we set up several biophysical assays for the identification of GSK-3β inhibitors capable of binding protein hotspots other than the ATP binding pocket or to the ATP binding pocket, but with an affinity able of competing with a reference binder. A phosphorylation activity assay on a panel of several kinases provided selectivity data that were further rationalized and corroborated by structural information on GSK-3β in complex with the hit compounds. In this study, we identified promising fragments, inhibitors of GSK-3β, while proposing an alternative screening workflow that allows facing the flaws that characterize the most common GSK-3β inhibitors through the identification of selective inhibitors and/or inhibitors able to modulate GSK-3β activity without leading to its complete inhibition | ||
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| 700 | 1 | |a Tripathi, Shailesh Kumar |e verfasserin |4 aut | |
| 700 | 1 | |a Veronesi, Marina |e verfasserin |4 aut | |
| 700 | 1 | |a Russo, Debora |e verfasserin |4 aut | |
| 700 | 1 | |a Penna, Ilaria |e verfasserin |4 aut | |
| 700 | 1 | |a Giabbai, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Bandiera, Tiziano |e verfasserin |4 aut | |
| 700 | 1 | |a Storici, Paola |e verfasserin |4 aut | |
| 700 | 1 | |a Girotto, Stefania |e verfasserin |4 aut | |
| 700 | 1 | |a Cavalli, Andrea |e verfasserin |4 aut | |
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