Description:
<jats:sec><jats:title>Background and Purpose</jats:title><jats:p>The <jats:styled-content style="fixed-case">E</jats:styled-content>ph receptor tyrosine kinases and their ephrin ligands are key players in tumorigenesis and many reports have correlated changes in their expression with a poor clinical prognosis in many solid tumours. Agents targeting the <jats:styled-content style="fixed-case">E</jats:styled-content>ph‐ephrin system might emerge as new tools useful for the inhibition of different components of cancer progression. Even if different classes of small molecules targeting <jats:styled-content style="fixed-case">E</jats:styled-content>ph‐ephrin interactions have been reported, their use is hampered by poor chemical stability and low potency. Stable and potent ligands are crucial to achieve robust pharmacological performance.</jats:p></jats:sec><jats:sec><jats:title>Experimental Approach</jats:title><jats:p><jats:styled-content style="fixed-case">U</jats:styled-content>ni<jats:styled-content style="fixed-case">PR</jats:styled-content>129 (the <jats:styled-content style="fixed-case">L</jats:styled-content>‐homo‐<jats:styled-content style="fixed-case">T</jats:styled-content>rp conjugate of lithocholic acid) was designed by means of computational methods, synthetized and tested for its ability to inhibit the interaction between the <jats:styled-content style="fixed-case">E</jats:styled-content>ph<jats:styled-content style="fixed-case">A</jats:styled-content>2 receptor and the ephrin‐<jats:styled-content style="fixed-case">A</jats:styled-content>1 ligand in an <jats:sc>elisa</jats:sc> binding study. The ability of <jats:styled-content style="fixed-case">U</jats:styled-content>ni<jats:styled-content style="fixed-case">PR</jats:styled-content>129 to disrupt <jats:styled-content style="fixed-case">E</jats:styled-content>ph<jats:styled-content style="fixed-case">A</jats:styled-content>2‐ephrin‐<jats:styled-content style="fixed-case">A</jats:styled-content>1 interaction was functionally evaluated in a prostate adenocarcinoma cell line and its anti‐angiogenic effect was tested <jats:italic>in vitro</jats:italic> using cultures of <jats:styled-content style="fixed-case">HUVECs</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Key Results</jats:title><jats:p><jats:styled-content style="fixed-case">U</jats:styled-content>ni<jats:styled-content style="fixed-case">PR</jats:styled-content>129 disrupted <jats:styled-content style="fixed-case">E</jats:styled-content>ph<jats:styled-content style="fixed-case">A</jats:styled-content>2‐ephrin‐<jats:styled-content style="fixed-case">A</jats:styled-content>1 interaction with <jats:styled-content style="fixed-case">K</jats:styled-content><jats:sub>i</jats:sub> = 370 nM in an <jats:sc>elisa</jats:sc> binding assay and with low micromolar potency in cellular functional assays, including inhibition of <jats:styled-content style="fixed-case">E</jats:styled-content>ph<jats:styled-content style="fixed-case">A</jats:styled-content>2 activation, inhibition of <jats:styled-content style="fixed-case">PC</jats:styled-content>3 cell rounding and disruption of <jats:italic>in vitro</jats:italic> angiogenesis, without cytotoxic effects.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Implications</jats:title><jats:p>The discovery of <jats:styled-content style="fixed-case">U</jats:styled-content>ni<jats:styled-content style="fixed-case">PR</jats:styled-content>129 represents not only a major advance in potency compared with the existing <jats:styled-content style="fixed-case">E</jats:styled-content>ph‐ephrin antagonists but also an improvement in terms of cytotoxicity, making this molecule a useful pharmacological tool and a promising lead compound.</jats:p></jats:sec>