Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA.
Early Translation Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA.
Commun Biol. 2022 Nov 4;5(1):1183. doi: 10.1038/s42003-022-04143-9.
The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation. In this report, we describe the discovery of a small molecule series of RXFP2 agonists. These compounds are highly potent, efficacious, and selective RXFP2 allosteric agonists that induce gubernacular invagination in mouse embryos, increase mineralization activity in human osteoblasts in vitro, and improve bone trabecular parameters in adult mice. The described RXFP2 agonists are orally bioavailable and display favorable pharmacokinetic properties, which allow for future evaluation of the therapeutic benefits of modulating RXFP2 activation in disease models.
松弛素/胰岛素样家族肽受体 2（RXFP2）属于 A 类 G 蛋白偶联受体（GPCR）家族，它是胰岛素样因子 3 肽（INSL3）的唯一已知靶标。该配体-受体对在睾丸下降的腹腔期 gubernacular 韧带发育中的重要性已得到充分证实。最近，RXFP2 被认为与维持健康的骨形成有关。在本报告中，我们描述了一系列小分子 RXFP2 激动剂的发现。这些化合物是高效、有效的和选择性的 RXFP2 别构激动剂，可诱导小鼠胚胎中的 gubernacular 内陷，增加体外人成骨细胞的矿化活性，并改善成年小鼠的骨小梁参数。所描述的 RXFP2 激动剂具有口服生物利用度，并表现出良好的药代动力学特性，这允许在疾病模型中进一步评估调节 RXFP2 激活的治疗益处。
