LRH-1 Inverse agonists (TES Pharma)

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.

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.