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

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