Identification\nof Small-Molecule Antagonists Targeting\nthe Growth Hormone Releasing Hormone Receptor (GHRHR)

The growth hormone-releasing\nhormone receptor (GHRHR)\nbelongs to\nClass B1 of G protein-coupled receptors (GPCRs). Class B1 GPCR peptides\nsuch, as growth hormone-releasing hormone (GHRH), have been proposed\nto bind in a two-step model, where first the C-terminal region of\nthe peptide interacts with the extracellular domain of the receptor\nand, subsequently, the N-terminus interacts with the seven transmembrane\ndomain of the receptor, resulting in activation. The GHRHR has recently\nbeen highlighted as a promising drug target toward several types of\ncancer and has been shown to be overexpressed in prostate, breast,\npancreatic, and ovarian cancer. Indeed, peptide GHRHR antagonists\nhave displayed promising results in many cancer models. However, no\nnonpeptide GHRHR-targeting compounds have yet been identified. We\nhave utilized several computational tools to target GHRHR and identify\npotential small-molecule compounds directed at this receptor. These\ncompounds were validated <i>in vitro</i> using a cyclic\nadenosine monophosphate (cAMP) ELISA to measure activity at the GHRHR. <i>In vitro</i> results suggest that several of the novel small-molecule\ncompounds could inhibit GHRH-induced cAMP accumulation. Preliminary\nanalysis of the specificity/selectivity of one of the most effective\nhit compounds indicated that the effect seen was via inhibition of\nthe GHRHR. We therefore report the first nonpeptide antagonists of\nGHRHR and propose a structural basis for inhibition induced by the\ncompounds, which may assist in the future design of lead GHRHR compounds\nfor treating disorders attributed to dysregulated/aberrant GHRHR signaling.