ETV plays an important role in tumorigenesis
ETV5 plays an important role in tumorigenesis and metastasis. For example, chromosomal rearrangement of ETV5 which results in increased ETV5 level is believed as a common event driving human prostate cancer (Helgeson et al., 2008; Huang and Waknitz, 2009). Ghrelin/acyl-ghrelin also plays an important role in prostate cancer proliferation (Yeh et al., 2005). GOAT/ghrelin system is implicated in the cancer progression. The GOAT enzyme level is up-regulated in prostate cancer and correlated with aggressiveness and metabolic conditions in prostate cancer patient (Hormaechea-Agulla et al., 2016). These findings suggest that ETV5-GOAT/ghrelin axis has a potential role in cancer pathophysiology in addition to energy balance and appetite control.
Declaration of interests
Ghrelin, the natural ligand of the Growth Hormone Secretagogue Receptor type 1a (GHS-R1a), was recently discovered and characterized. Its main biological activities were found to be the stimulation of both growth hormone release and food intake. Ghrelin also regulates the metabolic balance by decreasing fat use, affecting body weight and adiposity. Thus, ghrelin functions as an orexigenic hormone and it can be of interest to find agonists and antagonists of its receptor. Before the discovery of ghrelin, research focused on the finding of agonists able to elicit the stimulation of GH secretion. Among many compounds, we can cite the peptidic precursor component GHRP-6 described by Bowers, the non peptidic Merck compound, MK-0677, which allowed the characterization of the GHS-R1a in its S labeled version, and the CP-424,391 (or Capromorelin), developed by Pfizer. Our team also described the JMV 1843, a pseudo-peptide which was able to stimulate GH secretion by oral administration in man. This Mesoridazine Besylate will be soon commercialized for the diagnostic of GH deficiency in adults. When multiple ghrelin biological activities were exhibited, it appears that antagonist (and/or inverse agonist) compounds of the GHS-R1a receptor could be useful to treat obesity, for example. Ipsen developed ghrelin analogs and identified a competitive GHS-R1a antagonist, BIM 28163, while Tranzyme Pharma has extensively claimed conformationally defined macrocyclic compounds incorporating peptides as modulators of the GHS-R1a, including antagonists. Numerous nonpeptide small molecules such as benzodiazepine, piperazine bisamide, azaquinazolinone and indolinone derivatives have been described as potent antagonists of the ghrelin receptor. In our effort to find new ghrelin receptor ligands, we recently described a family of peptidomimetics based on a decorated 1,2,4-triazole scaffold that led to potent agonists and antagonists of this receptor., , These compounds were synthesized from ()tryptophan residue as starting material and present in their final structure only one asymmetric carbon atom, whose configuration was controlled during the synthetic process. Replacement of the α-aminoisobutyryl (Aib) moiety, a common feature often present in GHS-R1a ligands,, , by groups such as glycyl, propyl, isonipecotyl or piperazyl-2-carbonyl groups was first explored. One of our front runners, compound JMV 2959 (compound , ), a trisubstituted 1,2,4-triazole comprised of a glycyl group in place of the Aib moiety, was found to be a potent GHS-R1a antagonist. Therefore has been extensively studied in various in vivo animal models and exhibits a large range of interesting properties such as suppression of food intake induced by ghrelin or by fasting and suppression of fat mass accumulation. It also presents in vivo effects on addictive behavior, providing evidence that the central ghrelin signaling system is required in the reward induced by addictive drugs such as alcohol, amphetamine and cocaine., When replacing the glycine residue on the N-terminal part of compound by a picolinic moiety, we obtained a very potent antagonist (compound , ). As shown in , the pharmacokinetic studies of the two compounds and exhibited a very different pattern. Indeed, compound showed a much better pharmacokinetic profile than compound , with a high maximal plasma concentration () reached 5h after administration and a high AUC value reflecting a long drug exposure to the body with a slow clearance.