2. Academic Validation
  3. Enhancing the activity of γ-hydroxy lactone derivatives as innovative peroxisome proliferator-activated receptor γ non-agonists inhibiting cyclin-dependent kinase 5-mediated phosphorylation

Enhancing the activity of γ-hydroxy lactone derivatives as innovative peroxisome proliferator-activated receptor γ non-agonists inhibiting cyclin-dependent kinase 5-mediated phosphorylation

  • Eur J Med Chem. 2025 Aug 5:292:117657. doi: 10.1016/j.ejmech.2025.117657.
Giulia Cazzaniga 1,  Davide Capelli 2,  Roberta Montanari 2,  Enrico Mario Alessandro Fassi 3,  Giovanni Grazioso 3,  Andrea Tresoldi 3,  Francesca Rinaldi 4,  Enrica Calleri 4,  Ivan Bassanini 5,  Sergio Romeo 6,  Mariangela Garofalo 7,  Matteo Mori 8,  Fiorella Meneghetti 3,  Stefania Villa 3
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133, Milano, Italy; Department of Science and High Technology, University of Insubria, via Valleggio 9, 22100, Como, Italy.
  • 2 Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Strada Provinciale 35d, n. 9-00010, Montelibretti, 34149, Rome, Italy.
  • 3 Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133, Milano, Italy.
  • 4 Department of Drug Sciences, University of Pavia, via T. Taramelli 12, 27100, Pavia, Italy.
  • 5 Istituto di Scienze e Tecnologie Chimiche "Giulio Natta", Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131, Milano, Italy.
  • 6 Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133, Milano, Italy; Istituto di Scienze e Tecnologie Chimiche "Giulio Natta", Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131, Milano, Italy.
  • 7 Department of Pharmaceutical Sciences, University of Padova, via F. Marzolo 5, 35131, Padova, Italy.
  • 8 Department of Pharmaceutical Sciences, University of Milan, via L. Mangiagalli 25, 20133, Milano, Italy. Electronic address: matteo.mori@unimi.it.
PMID: 40318479 DOI: 10.1016/j.ejmech.2025.117657
Abstract

Insulin resistance (IR) is a pathological condition in which tissues exhibit a reduced response to normal or elevated levels of Insulin. Type 2 diabetes mellitus (T2DM) and Metabolic Syndrome are the most prevalent disorders associated with IR. Most of the glitazones, traditional anti-diabetic drugs acting as Peroxisome Proliferator-activated Receptor γ (PPARγ) agonists, have been withdrawn from the market. To mitigate the serious adverse effects associated with PPARγ agonism, a new opportunity is represented by the 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 Ser245. Recently, we identified 4-(4-bromophenyl)-3-hydroxy-5-(3-hydroxyphenyl)furan-2(5H)-one (I) as a PPARγ non-agonist, capable of blocking the phosphorylation of the enzyme without direct effects on either CDK5 or PPARγ. Here, we isolated the two enantiomers of I, unambiguously defined their absolute configuration through single crystal X-ray diffraction and demonstrated by Grating-Coupled Interferometry binding assays that both (S)-I and (R)-I exhibited comparable affinity for PPARγ. Then, a library of 12 analogs was designed through structure-based modifications, optimizing the interactions within the ligand-binding domain. GCI analysis identified derivative 11, featuring an oxyacetic group in place of the initial hydroxyl function of the reference compound I, as the most promising candidate (KD = 186 nM). The crystal structure of the PPARγ-LBD/11 complex revealed a hydrogen bond interaction with Arg280, further stabilizing the binding conformation. These findings highlight the potential of γ-hydroxy lactone derivatives as PPARγ modulators and provide a foundation for future drug development targeting IR.

Keywords

Binding affinity; CDK5; Enantiomeric resolution; Insulin resistance; Ligand-protein complex; PPARγ non-agonists; SBDD; SC-XRD.

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