TY - JOUR
T1 - Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design
AU - Mays, Suzanne G.
AU - Flynn, Autumn R.
AU - Cornelison, Jeffery L.
AU - Okafor, C. Denise
AU - Wang, Hongtao
AU - Wang, Guohui
AU - Huang, Xiangsheng
AU - Donaldson, Heather N.
AU - Millings, Elizabeth J.
AU - Polavarapu, Rohini
AU - Moore, David D.
AU - Calvert, John W.
AU - Jui, Nathan T.
AU - Ortlund, Eric A.
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/12/26
Y1 - 2019/12/26
N2 - 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.
AB - 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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U2 - 10.1021/acs.jmedchem.9b00753
DO - 10.1021/acs.jmedchem.9b00753
M3 - Article
C2 - 31419141
AN - SCOPUS:85072634620
SN - 0022-2623
VL - 62
SP - 11022
EP - 11034
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -