Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition
Articolo
Data di Pubblicazione:
2023
Citazione:
Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition / D. Capelli, G. Cazzaniga, M. Mori, A. Laghezza, F. Loiodice, M. Quaglia, E. Negro, F. Meneghetti, S. Villa, R. Montanari. - In: BIOMOLECULES. - ISSN 2218-273X. - 13:4(2023 Apr 19), pp. 694.1-694.18. [10.3390/biom13040694]
Abstract:
PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature). In this paper, we report the identification of new γ-hydroxy-lactone-based PPARγ binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPARγ, and one of them prevents Ser245 PPARγ phosphorylation by acting mainly on PPARγ stabilization and exerting a weak CDK5 inhibitory effect.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
X-ray crystallography; drug design; heterocycle; PPARγ phosphorylation;
Elenco autori:
D. Capelli, G. Cazzaniga, M. Mori, A. Laghezza, F. Loiodice, M. Quaglia, E. Negro, F. Meneghetti, S. Villa, R. Montanari
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