Optimization of EphA2 antagonists based on a lithocholic acid core led to the identification of UniPR505, a new 3α-carbamoyloxy derivative with antiangiogenetic properties

  • Eur J Med Chem. 2020 Mar 1;189:112083. doi: 10.1016/j.ejmech.2020.112083.
Matteo Incerti  1 ,  Simonetta Russo  1 ,  Miriam Corrado  1 ,  Carmine Giorgio  1 ,  Vigilio Ballabeni  1 ,  Paola Chiodelli  2 ,  Marco Rusnati  2 ,  Laura Scalvini  1 ,  Donatella Callegari  1 ,  Riccardo Castelli  1 ,  Federica Vacondio  1 ,  Francesca Ferlenghi  1 ,  Massimiliano Tognolini  3 ,  Alessio Lodola  4
Affiliations
  • 1. Department of Food and Drug, University of Parma, 43124, Parma, Italy.
  • 2. Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
  • 3. Department of Food and Drug, University of Parma, 43124, Parma, Italy. Electronic address: [email protected].
  • 4. Department of Food and Drug, University of Parma, 43124, Parma, Italy. Electronic address: [email protected].
PMID: 32000051 DOI: 10.1016/j.ejmech.2020.112083
Abstract

The EphA2 receptor has been validated in animal models as new target for treating tumors depending on angiogenesis and vasculogenic mimicry. In the present work, we extended our current knowledge on structure-activity relationship (SAR) data of two related classes of antagonists of the EphA2 receptor, namely 5β-cholan-24-oic acids and 5β-cholan-24-oyl l-β-homotryptophan conjugates, with the aim to develop new antiangiogenic compounds able to efficiently prevent the formation of blood vessels. As a result of our exploration, we identified UniPR505, N-[3α-(Ethylcarbamoyl)oxy-5β-cholan-24-oyl]-l-β-homo-tryptophan (compound 14), as a submicromolar antagonist of the EphA2 receptor capable to block EphA2 phosphorylation and to inhibit neovascularization in a chorioallantoic membrane (CAM) assay.

Keywords
Angiogenesis; EphA2; Lithocholic acid; Molecular modelling; Protein-protein interaction; SAR.
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