Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition

Abstract

Article history:Received Revised Accepted Available online LRH-1 is a nuclear receptor that regulates lipid metabolism and homeostasis, making it an attractive target for the treatment of diabetes and non-alcoholic fatty liver disease. Building on recent structural information about ligand binding from our labs, we have designed a series of new LRH-1 agonists that further engage LRH-1 through added polar interactions. While the current synthetic approach to this scaffold has, in large part, allowed for decoration of the agonist core, significant variation of the bridgehead substituent is mechanistically precluded. We have developed a new synthetic approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand-binding pocket to alter LRH-1 target gene expression..

The nuclear receptor LRH-1 discriminates between ligands using distinct allosteric signaling circuits

“…We have shown that polar groups at R1 in 6HP ligands act as anchors to lock this class of compound in very similar binding poses. (22,(24)(25)(26)(27). Therefore, ligands without experimentally determined structures were docked into the binding pocket such that the 6HP cores were aligned (Figure 1C).…”

“…Finally, NRs interact with many coregulators, which likely utilize different allosteric mechanisms. Tif2 has been crystallized with many LRH-1-ligand complexes, and it interacts with LRH-1 in the presence of both strong and weak agonists and when the receptor is unliganded (20, 21,[24][25][26]29,36,37). This makes Tif2 well-suited for studying allosteric signaling by ligands with a wide range of activities.…”

A phospholipid mimetic targeting LRH-1 ameliorates colitis

“…In addition to demarking differences between active and inactive compounds, the coregulator recruitment pattern of 9CA and 10CA also differs from that of 6N and 6Na, LRH-1 agonists that share the 6HP scaffold but are modified elsewhere on the molecule (Figure S1) (Cornelison et al, 2020;Mays et al, 2019). Unsupervised hierarchical clustering of the data shows a striking separation by ligand class: the most structurally similar ligands cluster together (Figure 3D).…”

“…In contrast, the synthetic LRH-1 agonist RJW100 binds deep in the pocket (Figure 1A). We previously focused on strengthening deep pocket interactions made by RJW100, resulting in the discovery of the agonists 6N and 6Na (Figure S1) (Cornelison et al, 2020;Mays et al, 2019). For the PL mimics, we used an alternative approach, seeking to promote interactions near the mouth of the pocket.…”

LRH-1/NR5A2 regulates the PTGS2-PGE2-PTGER1 signalling axis contributing to islet survival and antidiabetic actions of the agonist BL001

“…Accordingly, administration of dilauroyl phosphatidylcholine (DLPC, the natural ligand of LRH-1/NR5A2) was shown to decrease hepatic steatosis and improve glucose homeostasis in two mouse models of insulin resistance and T2DM 10 . These results prompted the development of hybrid phospholipid mimics as well as small non-polar bicyclic compounds that act as potent LRH-1/NR5A2 ligands 11,12,13 . Based on one of these published structures able to bind to the ligand binding pocket of NR5A2/LRH1, we synthesized a small chemical agonist of LRH-1/NR5A2, denoted as BL001, and assessed its anti-diabetic therapeutic value for T1DM.…”