Amino Acid Conjugates of Lithocholic Acid As Antagonists of the EphA2 Receptor

Journal of Medicinal Chemistry (Impact Factor: 5.45). 03/2013; 56(7). DOI: 10.1021/jm301890k
Source: PubMed


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.

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Available from: Alessio Lodola, Jul 15, 2014
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    • "EphrinA1, an angiogenic protein stimulated by pro-inflammatory cytokines, promotes tumorigenesis through interaction with the EphA2-R (Pandey et al., 1995; Cheng et al., 2002; Brantley-Sieders et al., 2004a,b, 2006; Pasquale, 2008; Miao et al., 2009; Beauchamp and Debinski, 2011). Antagonism of the EphA2-R with lithocholic acid blocks EphA2-R phosphorylation and reduces cancer cell growth (Incerti et al., 2013). Furthermore, the absence of the EphA2-R in mice confers a predilection for hyper-responsiveness to allergens demonstrated by increased inflammation (Okazaki et al., 2009). "
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