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The role of the Eph-ephrin system in the etiology of pathological conditions has been consolidated throughout the years. In this context, approaches directed against this signaling system, intended to modulate its activity, can be strategic therapeutic opportunities. Currently, the most promising class of compounds able to interfere with the Eph receptor-ephrin protein interaction is composed of synthetic derivatives of bile acids. In the present review, we summarize the progresses achieved, in terms of chemical expansions and structure-activity relationships, both in the steroidal core and the terminal carboxylic acid group, along with the pharmacological characterization for the most promising Eph-ephrin antagonists in in vivo settings.

1. In a mass balance study, six healthy male volunteers received a single oral dose of 4 mg (14)C-labelled emedastine difumarate. The pharmacokinetics of the total radioactivity and unchanged drug were assessed over 48 h. Urinary and faecal excretion were measured over 120 h. Additionally, urinary metabolites were investigated. 2. In a single- and multiple-dose pharmacokinetic study, nine male and nine female healthy volunteers received 2 mg oral emedastine difumarate b.i.d. or 4 mg o.d. for 7 consecutive days. The plasma pharmacokinetics were assessed on day 1 and at steady-state. 3. The mass balance study demonstrated almost complete gastrointestinal absorption of the administered dose. A total of 94.2% of the radioactivity was eliminated via the kidneys. Unchanged emedastine in the urine accounted for <5% of dose. 5-Hydroxy, 6-hydroxy and N-oxide metabolites previously identified in the Japanese were present in Caucasian subjects. 4. AUC after single and multiple dosing were dose-proportional. On day 7, no statistical difference in AUC(0-24) could be detected between the two regimens, with AUC = 70.6 +/- 36.1 and 71.7 +/- 52.3 ng h ml(-1), respectively. There were no gender differences in the pharmacokinetics of emedastine. 5. The results corroborate the use of emedastine in a Caucasian population and support the extrapolation of safety and efficacy data from Asians to Caucasians.

Angiogenesis, the formation of new blood vessels from preexisting ones, is crucial for tumor growth and metastatization, and is considered a promising therapeutic target. Unfortunately, drugs directed against a specific proangiogenic growth factor or receptor turned out to be of limited benefit for oncology patients, likely due to the high biochemical redundancy of the neovascularization process. In this scenario, multitarget compounds that are able to simultaneously tackle different proangiogenic pathways are eagerly awaited. UniPR1331 is a 3β-hydroxy-Δ5-cholenic acid derivative, which is already known to inhibit Eph–ephrin interaction. Here, we employed an analysis pipeline consisting of molecular modeling and simulation, surface plasmon resonance spectrometry, biochemical assays, and endothelial cell models to demonstrate that UniPR1331 directly interacts with the vascular endothelial growth factor receptor 2 (VEGFR2) too. The binding of UniPR1331 to VEGFR2 prevents its interaction with the natural ligand vascular endothelial growth factor and subsequent autophosphorylation, signal transduction, and in vitro proangiogenic activation of endothelial cells. In vivo, UniPR1331 inhibits tumor cell-driven angiogenesis in zebrafish. Taken together, these data shed light on the pleiotropic pharmacological effect of UniPR1331, and point to Δ5-cholenic acid as a promising molecular scaffold for the development of multitarget antiangiogenic compounds.

The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.