Development of the First Low Nanomolar Liver Receptor Homolog‑1 Agonist through Structure-guided Design

As
a key regulator of metabolism and inflammation, the orphan nuclear
hormone receptor, liver receptor homolog-1 (LRH-1), has potential
as a therapeutic target for diabetes, nonalcoholic fatty liver disease,
and inflammatory bowel diseases (IBD). Discovery of LRH-1 modulators
has been difficult, in part due to the tendency for synthetic compounds
to bind unpredictably within the lipophilic binding pocket. Using
a structure-guided approach, we exploited a newly discovered polar
interaction to lock agonists in a consistent orientation. This enabled
the discovery of the first low nanomolar LRH-1 agonist, one hundred
times more potent than the best previous modulator. We elucidate a
novel mechanism of action that relies upon specific polar interactions
deep in the LRH-1 binding pocket. In an organoid model of IBD, the
new agonist increases expression of LRH-1-controlled steroidogenic
genes and promotes anti-inflammatory gene expression changes. These
studies constitute major progress in developing LRH-1 modulators with
potential clinical utility.