1. Academic Validation
  2. Pharmacological evaluation of new bioavailable small molecules targeting Eph/ephrin interaction

Pharmacological evaluation of new bioavailable small molecules targeting Eph/ephrin interaction

  • Biochem Pharmacol. 2018 Jan;147:21-29. doi: 10.1016/j.bcp.2017.11.002.
Carmine Giorgio 1 Matteo Incerti 1 Miriam Corrado 1 Marco Rusnati 2 Paola Chiodelli 2 Simonetta Russo 1 Donatella Callegari 1 Francesca Ferlenghi 1 Vigilio Ballabeni 1 Elisabetta Barocelli 1 Alessio Lodola 3 Massimiliano Tognolini 4
Affiliations

Affiliations

  • 1 Department of Food and Drugs, University of Parma, 43124 Parma, Italy.
  • 2 Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
  • 3 Department of Food and Drugs, University of Parma, 43124 Parma, Italy. Electronic address: alessio.lodola@unipr.it.
  • 4 Department of Food and Drugs, University of Parma, 43124 Parma, Italy. Electronic address: massimiliano.tognolini@unipr.it.
Abstract

Eph/ephrin system is an emerging target for Cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129. These two compounds acted as competitive and reversible antagonists of all Eph Receptors reducing both Ephrin-A1 and -B1 binding to EphAs and EphBs receptors in the low micromolar range. The compounds acted as antagonists inhibiting ephrin-A1-dependent EphA2 activation and UniPR139 exerted an anti-angiogenic effect, inhibiting HUVEC tube formation in vitro and VEGF-induced vessel formation in the chick chorioallantoic membrane assay. Finally, the oral bioavailability of UniPR139 represents a step forward in the search of molecules targeting the Eph/ephrin system and offers a new pharmacological tool useful for future in vivo studies.

Keywords

Angiogenesis; Eph kinase; Ephrin; Protein-protein interaction (PPI); VEGF.

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