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

Incerti, Matteo; Tognolini, Massimiliano; Russo, Simonetta; Pala, Daniele; Giorgio, Carmine; Hassan-Mohamed, Iftiin; Noberini, Roberta; Pasquale, Elena B.; Vicini, Paola; Piersanti, Silvia; Rivara, Silvia; Barocelli, Elisabetta; Mor, Marco; Lodola, Alessio

doi:10.1021/jm301890k

Cited by 50 publications

(78 citation statements)

References 46 publications

(128 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…compound 2, Fig. 1, pIC 50 ¼ 5.69 [23]) corroborating the notion that 3b-hydroxy-D 5 -cholenic acid is an effective bioisostere of lithocholic acid.…”

Section: Resultssupporting

confidence: 75%

“…compounds 2 and 3 reported in Fig. 1) [23,24], 10 was able to inhibit ephrin binding to all members of the Eph receptor family with comparable inhibitory potency (Fig. 10).…”

Section: Selectivity Profile Of Compound 10mentioning

confidence: 82%

“…ELISA assays were performed as previously described [23]. 96-well ELISA high binding plates (Costar #2592) were incubated overnight at 4 C with 100 mL/well of 1 mg mL À1 EphA2-Fc (R&D 639-A2) diluted in sterile phosphate buffered saline (PBS, 0.2 g/ L KCl, 8.0 g/L NaCl, 0.2 g L À1 KH 2 PO 4 , 1.15 g/L Na 2 HPO 4 , pH 7.4).…”

Section: Elisa Assays and Ki/ic 50 Determination On Epha2mentioning

confidence: 99%

“…Starting from lithocholic acid (1), we recently prepared a set of conjugates with amino acids able to interfere with the EphA2-eephrin-A1 interaction with potency in the micromolar range [23].…”

Section: Introductionmentioning

confidence: 99%

“…1, [23]) and N-(3a-hydroxy-5b-cholan-24-oyl)-Lb-homotryptophan (UniPR129, compound 3, Fig. 1, [24]).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Eph–ephrin system

Castelli

Tognolini

Vacondio

et al. 2015

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

The Eph receptor-ephrin system is an emerging target for the development of novel anti-angiogenic therapies. Research programs aimed at developing small-molecule antagonists of the Eph receptors are still in their initial stage as available compounds suffer from pharmacological drawbacks, limiting their application in vitro and in vivo. In the present work, we report the design, synthesis and evaluation of structure-activity relationships of a class of Δ(5)-cholenoyl-amino acid conjugates as Eph-ephrin antagonists. As a major achievement of our exploration, we identified N-(3β-hydroxy-Δ(5)-cholen-24-oyl)-L-tryptophan (UniPR1331) as the first small molecule antagonist of the Eph-ephrin system effective as an anti-angiogenic agent in endothelial cells, bioavailable in mice by the oral route and devoid of biological activity on G protein-coupled and nuclear receptors targeted by bile acid derivatives.

show abstract

“…compound 2, Fig. 1, pIC 50 ¼ 5.69 [23]) corroborating the notion that 3b-hydroxy-D 5 -cholenic acid is an effective bioisostere of lithocholic acid.…”

Section: Resultssupporting

confidence: 75%

“…compounds 2 and 3 reported in Fig. 1) [23,24], 10 was able to inhibit ephrin binding to all members of the Eph receptor family with comparable inhibitory potency (Fig. 10).…”

Section: Selectivity Profile Of Compound 10mentioning

confidence: 82%

Section: Elisa Assays and Ki/ic 50 Determination On Epha2mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…1, [23]) and N-(3a-hydroxy-5b-cholan-24-oyl)-Lb-homotryptophan (UniPR129, compound 3, Fig. 1, [24]).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Eph–ephrin system

Castelli

Tognolini

Vacondio

et al. 2015

European Journal of Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Exploiting Free‐Energy Minima to Design Novel EphA2 Protein–Protein Antagonists: From Simulation to Experiment and Return

Russo

Callegari

Incerti

et al. 2016

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

Target Hopping as a Useful Tool for the Identification of Novel EphA2 Protein–Protein Antagonists

et al. 2013

Self Cite

View full text Add to dashboard Cite

Lithocholic acid (LCA), a physiological ligand for the nuclear receptor FXR and the G-protein-coupled receptor TGR5, has been recently described as an antagonist of the EphA2 receptor, a key member of the ephrin signalling system involved in tumour growth. Given the ability of LCA to recognize FXR, TGR5, and EphA2 receptors, we hypothesized that the structural requirements for a small molecule to bind each of these receptors might be similar. We therefore selected a set of commercially available FXR or TGR5 ligands and tested them for their ability to inhibit EphA2 by targeting the EphA2-ephrin-A1 interface. Among the selected compounds, the stilbene carboxylic acid GW4064 was identified as an effective antagonist of EphA2, being able to block EphA2 activation in prostate carcinoma cells, in the micromolar range. This finding proposes the "target hopping" approach as a new effective strategy to discover new protein-protein interaction inhibitors.

show abstract

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

Cited by 50 publications

References 46 publications

Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Eph–ephrin system

Δ5-Cholenoyl-amino acids as selective and orally available antagonists of the Eph–ephrin system

Exploiting Free‐Energy Minima to Design Novel EphA2 Protein–Protein Antagonists: From Simulation to Experiment and Return

Target Hopping as a Useful Tool for the Identification of Novel EphA2 Protein–Protein Antagonists

Contact Info

Product

Resources

About