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Identification of the First PPAR alpha/gamma Dual Agonist Able To Bind to Canonical and Alternative Sites of PPAR gamma and To Inhibit Its Cdk5-Mediated Phosphorylation

Abstract : A new series of derivatives of the PPAR alpha/gamma dual agonist 1 allowed us to identify the ligand (S)-6 as a potent partial agonist of both PPAR alpha and gamma subtypes. X-ray studies in PPAR gamma revealed two different binding modes of (S)-6 to the canonical site. However, (S)-6 was also able to bind an alternative site as demonstrated by transactivation assay in the presence of a canonical PPAR gamma antagonist and supported from docking experiments. This compound did not activate the PPAR gamma-dependent program of adipocyte differentiation inducing a very less severe lipid accumulation compared to rosiglitazone but increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Finally, (S)-6 inhibited the Cdk5-mediated phosphorylation of PPAR gamma at serine 273 that is currently considered the mechanism by which some PPAR gamma partial agonists exert antidiabetic effects similar to thiazolidinediones, without showing their typical side effects. This is the first PPAR alpha/gamma dual agonist reported to show this inhibitory effect representing the potential lead of a new class of drugs for treatment of dyslipidemic type 2 diabetes.
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https://hal-amu.archives-ouvertes.fr/hal-02068142
Contributor : Annick Prémilleux <>
Submitted on : Thursday, March 14, 2019 - 4:04:57 PM
Last modification on : Tuesday, May 26, 2020 - 7:00:52 AM

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Antonio Laghezza, Luca Piemontese, Carmen Cerchia, Roberta Montanari, Davide Capelli, et al.. Identification of the First PPAR alpha/gamma Dual Agonist Able To Bind to Canonical and Alternative Sites of PPAR gamma and To Inhibit Its Cdk5-Mediated Phosphorylation. Journal of Medicinal Chemistry, American Chemical Society, 2018, 61 (18), pp.8282-8298. ⟨10.1021/acs.jmedchem.8b00835⟩. ⟨hal-02068142⟩

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