title: Biochemical characterization of EphA2 antagonists with improved physico-chemical properties by cell-based assays and surface plasmon resonance analysis.
abstract: Amino acid conjugates of lithocholic acid (LCA) have been recently described as effective disruptors of the EphA2-ephrin-A1 interaction able to inhibit EphA2 phosphorylation in intact cells and thus able to block prometastatic responses such as cellular retraction and angiogenesis. However, these LCA-based compounds were significantly more potent at disrupting the EphA2-ephrin-A1 interaction than at blocking phenotype responses in cells, which might reflect an unclear mechanism of action or a metabolic issue responsible for a reduction of the compound concentration at the cell's surface. Through the synthesis of new compounds and their examination by a combination of cell-based assays and real-time interaction analysis by surface plasmon resonance, we showed at molecular level that l-tryptophan conjugates of lithocholic acid disrupt EphA2-ephrin-A1 interaction by targeting the EphA 2 receptor and that the presence of a polar group in position 3 of steroid scaffold is a key factor to increase the effective concentration of the compounds in cancer cell lines.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Giorgio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Russo
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Incerti
authors.affiliation: Dipartimento di Medicina Molecolare Traslazionale, Università degli Studi di Brescia, Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy.
authors.forename: Iftiin
authors.initials: I
authors.lastname: Hassan-Mohamed
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Perugia, Italy.
authors.forename: Antimo
authors.initials: A
authors.lastname: Gioiello
authors.affiliation: Dipartimento di Medicina Molecolare Traslazionale, Università degli Studi di Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy; Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, UK. Electronic address: alessio.lodola@unipr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parma, Italy. Electronic address: massimiliano.tognolini@unipr.it.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Tognolini
mesh_terms: D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D006801:Humans; D008095:Lithocholic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D062105:Molecular Docking Simulation / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance / Q000379:methods*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; C000600256:UniPR129; D008095:Lithocholic Acid; D014364:Tryptophan; D036104:Receptor, EphA2
keywords: Antagonist; Bile acid; Eph kinases; Ephrin; PPI