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The Eph receptor-ephrin system is an emerging target for the development of novel antiangiogenetic agents. We recently identified lithocholic acid (LCA) as a small molecule able to block EphA2-dependent signals in cancer cells, suggesting that its (5β)-cholan-24-oic acid scaffold can be used as a template to design a new generation of improved EphA2 antagonists. Here, we report the design and synthesis of an extended set of LCA derivatives obtained by conjugation of its carboxyl group with different α-amino acids. Structure-activity relationships indicate that the presence of a lipophilic amino acid side chain is fundamental to achieve good potencies. The l-Trp derivative (20, PCM126) was the most potent antagonist of the series disrupting EphA2-ephrinA1 interaction and blocking EphA2 phosphorylation in prostate cancer cells at low μM concentrations, thus being significantly more potent than LCA. Compound 20 is among the most potent small-molecule antagonists of the EphA2 receptor.

Citation

Matteo Incerti, Massimiliano Tognolini, Simonetta Russo, Daniele Pala, Carmine Giorgio, Iftiin Hassan-Mohamed, Roberta Noberini, Elena B Pasquale, Paola Vicini, Silvia Piersanti, Silvia Rivara, Elisabetta Barocelli, Marco Mor, Alessio Lodola. Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. Journal of medicinal chemistry. 2013 Apr 11;56(7):2936-47

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PMID: 23489211

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