Abstract |
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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Authors | Matteo Incerti, Massimiliano Tognolini, Simonetta Russo, Daniele Pala, Carmine Giorgio, Iftiin Hassan-Mohamed, Roberta Noberini, Elena B Pasquale, Paola Vicini, Silvia Piersanti, Silvia Rivara, Elisabetta Barocelli, Marco Mor, Alessio Lodola |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 56
Issue 7
Pg. 2936-47
(Apr 11 2013)
ISSN: 1520-4804 [Electronic] United States |
PMID | 23489211
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amino Acids
- Lithocholic Acid
- Receptor, EphA2
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Topics |
- Adenocarcinoma
(pathology)
- Amino Acids
(chemistry)
- Enzyme-Linked Immunosorbent Assay
- Humans
- Lithocholic Acid
(chemistry, pharmacology)
- Male
- Models, Molecular
- Phosphorylation
- Prostatic Neoplasms
(pathology)
- Receptor, EphA2
(antagonists & inhibitors, metabolism)
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