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

  • J Med Chem. 2019 Dec 26;62(24):11022-11034. doi: 10.1021/acs.jmedchem.9b00753.
Suzanne G Mays  1 ,  Autumn R Flynn ,  Jeffery L Cornelison ,  C Denise Okafor  1 ,  Hongtao Wang  2 ,  Guohui Wang  2 ,  Xiangsheng Huang  2 ,  Heather N Donaldson  1 ,  Elizabeth J Millings  1 ,  Rohini Polavarapu ,  David D Moore  3 ,  John W Calvert ,  Nathan T Jui ,  Eric A Ortlund  1
Affiliations
  • 1. Department of Biochemistry , Emory University School of Medicine , Atlanta , Georgia 30322 , United States.
  • 2. Department of Pediatrics, Section of Gastroenterology , Baylor College of Medicine and Texas Children's Hospital , Houston , Texas 77030 , United States.
  • 3. Department of Molecular and Cell Biology , Baylor College of Medicine , Houston , Texas 77030 , United States.
PMID: 31419141 DOI: 10.1021/acs.jmedchem.9b00753
Abstract

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.

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