Biological Screening and Crystallographic Studies of Hydroxy -Lactone Derivatives to Investigate PPAR Phosphorylation Inhibition

PPAR gamma represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPAR gamma agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPAR gamma phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPAR gamma beta-sheet containing Ser273 (Ser245 in PPAR gamma isoform 1 nomenclature). In this paper, we report the identification of new gamma-hydroxy-lactone-based PPAR gamma binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPAR gamma, and one of them prevents Ser245 PPAR gamma phosphorylation by acting mainly on PPAR gamma stabilization and exerting a weak CDK5 inhibitory effect.