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.
NIH-5R01DK115213 Emory Catalyst Program 1F31DK122745
