Relaxin family peptide receptor 2 modulators as therapeutics

The relaxin family peptide receptor 2 (RXFP2) and its cognate peptide hormone agonist INSL3 play an important role in regulating bone homeostasis and male reproductive physiology. RXFP2 signaling increases osteoblast proliferation and bone mineralization. Additionally, RXFP2 activation in sperm serves as an anti- apoptotic signal and promotes sperm survival. In view of these important biological roles, we propose here to develop both activating ligands (agonists) and inhibitors (antagonists) as candidate therapeutic agents. Agonists will be useful for the treatment of osteoporosis, while antagonists could serve as male contraceptives. In each case, we believe our approach is highly differentiated from existing options. Osteoporosis affects approximately 10.2 million people in the United States. Although osteoporosis medications are available, these are limited by side effects and poor patient compliance. A long-acting (monthly) RXFP2 agonist could offer an improved path toward treating osteoporosis while limiting compliance issues. In addition, antagonism of RXFP2 could serve as an effective male contraceptive, with monthly dosing differentiating it from alternatives in terms of duration and reversibility. In preliminary studies, we have engineered an INSL3-based agonist that shows potent activation of RXFP2 signaling and a chimeric INSL3/5 hormone that acts as a competitive antagonist that blocks RXFP2 activation. The project aims to further develop two protein-based lead therapeutic candidates, agonists and antagonists targeting RXFP2, up to the point of a clinical development candidate.