title: Target hopping as a useful tool for the identification of novel EphA2 protein-protein antagonists.
abstract: Lithocholic acid (LCA), a physiological ligand for the nuclear receptor FXR and the G-protein-coupled receptor TGR5, has been recently described as an antagonist of the EphA2 receptor, a key member of the ephrin signalling system involved in tumour growth. Given the ability of LCA to recognize FXR, TGR5, and EphA2 receptors, we hypothesized that the structural requirements for a small molecule to bind each of these receptors might be similar. We therefore selected a set of commercially available FXR or TGR5 ligands and tested them for their ability to inhibit EphA2 by targeting the EphA2-ephrin-A1 interface. Among the selected compounds, the stilbene carboxylic acid GW4064 was identified as an effective antagonist of EphA2, being able to block EphA2 activation in prostate carcinoma cells, in the micromolar range. This finding proposes the "target hopping" approach as a new effective strategy to discover new protein-protein interaction inhibitors.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, V. le delle Scienze 27 A, 43124 Parma (Italy).
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Simonetta
authors.initials: S
authors.lastname: Russo
authors.forename: Riccardo
authors.initials: R
authors.lastname: Castelli
authors.forename: Iftiin
authors.initials: I
authors.lastname: Hassan-Mohamed
authors.forename: Carmine
authors.initials: C
authors.lastname: Giorgio
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
mesh_terms: D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D036382:Ephrin-A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008095:Lithocholic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000187:drug effects; D017434:Protein Structure, Tertiary; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D036382:Ephrin-A1; D007555:Isoxazoles; D008095:Lithocholic Acid; D036104:Receptor, EphA2; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C473772:GPBAR1 protein, human; C412815:GW 4064
keywords: drug design; protein-protein interactions; receptors; structure-activity relationships; virtual screening