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 - Funding Information:
This work was supported in part by the National Institutes of Health under the following awards: T32GM008602 (S.G.M.), F31DK111171 (S.G.M.), R01DK095750 (E.A.O.), R01DK114213 (E.A.O., N.T.J., J.W.C), P30DK056338 (Texas Medical Center Digestive Disease Center pilot, H.W.). The work was also supported by an Emory Catalyst Award (E.A.O., N.T.J), NASPGHAN transition award (H.W.), and USDA ARS 3092-5-001-057 (D.D.M.).
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 -
