Hyperprolactinemia is an endocrine pathology resulting from over-production of prolactin (PRL) by pituitary adenomas, and leading to various reproductive disorders. In addition, there is increasing evidence that PRL acts as a growth-promoter of breast and prostate tumors. Classical drugs blocking pituitary PRL production are not necessarily efficient in these pathological situations, which has encouraged the search for alternative ways of inhibiting the undesirable actions of PRL. Prolactin receptor (PRLR) antagonists, acting at the level of receptor activation rather than PRL production, are the most promising strategy. Based on the protein core of human (h)PRL or growth hormone (hGH), the other natural hPRLR ligand, a series of new variants have been engineered within the past couple of years, leading to various patent applications. Modifications of amino acid sequences involve single/multiple substitutions, truncations, or generation of fusion proteins. Three mechanisms of action have been reported for these PRLR antagonists: 1) inhibition of PRLR signaling by competition with endogenous PRL for receptor binding, 2) activation of specific PRLR signalling pathways resulting in actions opposite to those of wild-type hPRL, and 3) engineering of chimeric ligands targeting more than one receptor/cell type, in order to improve tumor-growth inhibition. Since none of these patented molecules is yet in clinical trials, their efficacy to treat PRL-dependent pathologies remains to be demonstrated in humans.
Keywords: Breast cancer, prostate cancer, hyperprolactinemia, growth hormone, G129R-hPRL, Δ1-9-G129R-hPRL, G129RhPRL, S179D-hPRL, induced-fit
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