A novel series of cysteine-dependent, allosteric inverse agonists of the nuclear receptor RORγt. Issue 6 (15th March 2020)

• Record Type: Journal Article
• Authors: Jiang, Xin; Dulubova, Irina; Reisman, Scott A.; Hotema, Martha; Lee, Chun-Yue I.; Liu, Liping; McCauley, Lyndsey; Trevino, Isaac; Ferguson, Deborah A.; Eken, Yigitcan; Wilson, Angela K.; Wigley, W. Christian; Visnick, Melean
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 6(2020)
• Publication Date: 2020-03-15
• Subjects: RORgγt inverse agonists -- IL-17 -- Autoimmune disease -- Th17 cell differentiation -- Molecular dynamics simulations -- Allosteric NR modulator; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.126967
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Inhibition of the nuclear receptor Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) is a promising strategy for the treatment of autoimmune diseases. In this paper, we describe a series of allosteric, cysteine-dependent, inverse agonists of RORγt. Site-directed mutagenesis and molecular dynamics simulations are supportive of a mechanism of action through specific binding to Cys476 on alpha helix 11 of the ligand binding domain (LBD). Representative compounds in the series selectively inhibit RORγt, potently suppress interleukin-17A (IL-17A) production by human CD4 + T cells, and inhibit T helper 17 (Th17) differentiation from human naïve CD4 + T cells. The advanced compound 13 is orally bioavailable and active at a dose of 3 mg/kg in a murine collagen-induced model of rheumatoid arthritis. Collectively, these data are supportive of the development of compound 13 in autoimmune diseases.