Development and Characterization of Novel LRH‐1 Antagonist Using Structural and Computational Techniques

Abstract

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.