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

Suzanne G. Mays, Autumn R. Flynn, Jeffery L. Cornelison, C. Denise Okafor, Hongtao Wang, Guohui Wang, Xiangsheng Huang, Heather N. Donaldson, Elizabeth J. Millings, Rohini Polavarapu, David D. Moore, John W. Calvert, Nathan T. Jui, Eric A. Ortlund

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11022-11034
Number of pages13
JournalJournal of Medicinal Chemistry
Volume62
Issue number24
DOIs
StatePublished - Dec 26 2019

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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    Mays, S. G., Flynn, A. R., Cornelison, J. L., Okafor, C. D., Wang, H., Wang, G., Huang, X., Donaldson, H. N., Millings, E. J., Polavarapu, R., Moore, D. D., Calvert, J. W., Jui, N. T., & Ortlund, E. A. (2019). Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design. Journal of Medicinal Chemistry, 62(24), 11022-11034. https://doi.org/10.1021/acs.jmedchem.9b00753