UniPR129 is a competitive small molecule Eph‐ephrin antagonist blocking in vitro angiogenesis at low micromolar concentrations. (28th August 2014)

• Record Type: Journal Article
• Authors: Hassan‐Mohamed, I; Giorgio, C; Incerti, M; Russo, S; Pala, D; Pasquale, E B; Zanotti, I; Vicini, P; Barocelli, E; Rivara, S; Mor, M; Lodola, A; Tognolini, M
• Is Part Of: British journal of pharmacology. Volume 171:Number 23(2014:Dec.)
• Page Start: 5195
• Page End: 5208
• Publication Date: 2014-08-28
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12669
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12669-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>The Eph 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 Eph‐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 Eph‐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.</p> </sec> <sec id="bph12669-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>UniPR129 (the L‐homo‐Trp conjugate of lithocholic acid) was designed by means of computational methods, synthetized and tested for its ability to inhibit the interaction between the EphA2 receptor and the ephrin‐A1 ligand in an <sc>elisa</sc> binding study. The ability of UniPR129 to disrupt EphA2‐ephrin‐A1 interaction was functionally evaluated in a prostate adenocarcinoma cell line and its anti‐angiogenic effect was tested <italic>in vitro</italic> using cultures of HUVECs.</p> </sec> <sec id="bph12669-sec-0003" sec-type="section"> <title>Key Results</title> <p>UniPR129 disrupted EphA2‐ephrin‐A1 interaction with K<sub>i</sub> = 370 nM in an <sc>elisa</sc> binding assay and with low micromolar potency in cellular functional assays, including inhibition of EphA2 activation, inhibition of PC3 cell rounding and disruption of <italic>in vitro</italic> angiogenesis, without cytotoxic effects.</p> </sec> <sec id="bph12669-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>The discovery of UniPR129 represents not only a major advance in potency compared with the existing Eph‐ephrin antagonists but also an improvement in terms of cytotoxicity, making this molecule a useful pharmacological tool and a promising lead compound.</p> </sec> </abstract>