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

Journal of Medicinal Chemistry (Impact Factor: 5.45). 03/2013; 56(7). DOI: 10.1021/jm301890k
Source: PubMed

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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Available from: Alessio Lodola, Jul 15, 2014
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    • "EphrinA1, an angiogenic protein stimulated by pro-inflammatory cytokines, promotes tumorigenesis through interaction with the EphA2-R (Pandey et al., 1995; Cheng et al., 2002; Brantley-Sieders et al., 2004a,b, 2006; Pasquale, 2008; Miao et al., 2009; Beauchamp and Debinski, 2011). Antagonism of the EphA2-R with lithocholic acid blocks EphA2-R phosphorylation and reduces cancer cell growth (Incerti et al., 2013). Furthermore, the absence of the EphA2-R in mice confers a predilection for hyper-responsiveness to allergens demonstrated by increased inflammation (Okazaki et al., 2009). "
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    ABSTRACT: EphrinA1-EphA-receptor signaling is protective during myocardial infarction (MI). The EphA2-receptor (EphA2-R) potentially mediates cardiomyocyte survival. To determine the role of the EphA2-R in acute non-reperfused myocardial injury in vivo, infarct size, inflammatory cell density, NF-κB, p-AKT/Akt, and MMP-2 protein levels, and changes in ephrinA1/EphA2-R gene expression profile were assessed 4 days post-MI in B6129 wild-type (WT) and EphA2-R-mutant (EphA2-R-M) mice lacking a functional EphA2-R. Fibrosis, capillary density, morphometry of left ventricular chamber and infarct dimensions, and cardiac function also were measured 4 weeks post-MI to determine the extent of ventricular remodeling. EphA2-R-M infarct size and area of residual necrosis were 31.7% and 113% greater than WT hearts, respectively. Neutrophil and macrophage infiltration were increased by 46% and 84% in EphA2-R-M hearts compared with WT, respectively. NF-κB protein expression was 1.9-fold greater in EphA2-R-M hearts at baseline and 56% less NF-κB after infarction compared with WT. EphA6 gene expression was 2.5-fold higher at baseline and increased 9.8-fold 4 days post-MI in EphA2-R-M hearts compared with WT. EphrinA1 gene expression in EphA2-R-M hearts was unchanged at baseline and decreased by 42% 4 days post-MI compared with WT hearts. EphA2-R-M hearts had 66.7% less expression of total Akt protein and 59% less p-Akt protein than WT hearts post-MI. EphA2-R-M hearts 4 weeks post-MI had increased chamber dilation and interstitial fibrosis and decreased MMP-2 expression and capillary density compared with WT. In conclusion, the EphA2-R is necessary to appropriately modulate the inflammatory response and severity of early injury during acute MI, thereby influencing the progression of ischemic cardiomyopathy.
    Frontiers in Physiology 04/2014; 5:132. DOI:10.3389/fphys.2014.00132 · 3.53 Impact Factor
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    ABSTRACT: The Eph-ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas the introduction of aromatic amino acids reduces the potency in displacement studies. The b-alanine derivative 4 was able to disrupt EphA2-ephrinA1 interaction in the micromolar range and to dose-dependently inhibit EphA2 activation on PC3 cells. These findings may help the design of novel EphA2 antagonists active on cancer cell lines.
    Molecules 10/2013; 18(10):13043-60. DOI:10.3390/molecules181013043 · 2.42 Impact Factor
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    ABSTRACT: Eph receptors are the largest class of kinase receptors and, together with their ligands ephrins, they have a primary role in embryogenesis. Their expression is deregulated in several cancer tissues and, in many cases, abnormal levels of these proteins are correlated to a poor prognosis. Recently, the Eph-ephrin system was found to be deregulated in a number of pathological processes, involving the nervous and cardiovascular systems, as well as facilitating the entry of several pathogens. The increasing body of evidence indicating the Eph-ephrin system as a target for the treatment of solid tumors, amyotrophic lateral sclerosis and diabetes is currently driving the efforts toward the development of pharmacological tools potentially able to treat these pathologies.
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