Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

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Reported here are conditions for the construction of spirocyclic piperidines from linear aryl halide precursors. These conditions employ a strongly-reducing organic photoredox catalyst, in combination with a trialkylamine reductant, to achieve formation of aryl radical species. Regioselective cyclization followed by hydrogen atom transfer afforded a range of complex spiropiperidines. This system efficiently operates under mild conditions, without the need for toxic reagents or precious metals.

Nuclear receptors are transcription factors that respond to external lipophilic signaling molecules by recruiting coactivators that enhance target gene expression. Liver receptor homolog‐1 (LRH‐1) is a nuclear receptor that drives ERα signaling and expression of cell cycle regulatory genes. LRH‐1 antagonists are therefore attractive potential therapeutics for the treatment of ERα positive and negative breast cancer. However, mechanistic studies exploring LRH‐1 antagonism are incredibly limited due to the lack of structural insight on the few existing compounds that decrease receptor activity. Using structure‐guided compound design, we have made modifications to the chemical scaffold of a highly potent LRH‐1 agonist to target and disrupt the region of the receptor responsible for coactivator binding. Our strategy effectively decreases LRH‐1 thermal stability, coactivator association, and transcriptional activity. Interestingly, molecular dynamics simulations reveal that antagonism is achieved through disruption of allosteric paths of communication unique to LRH‐1. Our work therefore characterizes a highly efficacious small molecule LRH‐1 antagonist and provides mechanistic insight into how signaling for this receptor can be effectively disrupted without large structural rearrangements.