7OFI

Ligand complex of RORg LBD

Summary for 7OFI

• Entry DOI: 10.2210/pdb7ofi/pdb
• Descriptor: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 2, (2~{R})-2-(4-ethylsulfonylphenyl)-~{N}-[4-[1,1,1,3,3,3-hexakis(fluoranyl)-2-oxidanyl-propan-2-yl]phenyl]-~{N}'-methyl-butanediamide, ... (6 entities in total)
• Functional Keywords: nuclear hormone receptor autoimmunity small molecule inhibitor inverse agonist ligand binding domain, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 33552.32

Authors

Xue, Y.,Aagaard, A.,Narjes, F. (deposition date: 2021-05-05, release date: 2022-03-16, Last modification date: 2024-01-31)

Primary citation

Narjes, F.,Llinas, A.,von Berg, S.,Jirholt, J.,Lever, S.,Pehrson, R.,Collins, M.,Malmberg, A.,Svanberg, P.,Xue, Y.,Olsson, R.I.,Malmberg, J.,Hughes, G.,Hossain, N.,Grindebacke, H.,Leffler, A.,Krutrok, N.,Back, E.,Ramnegard, M.,Lepisto, M.,Thunberg, L.,Aagaard, A.,McPheat, J.,Hansson, E.L.,Chen, R.,Xiong, Y.,Hansson, T.G.
AZD0284, a Potent, Selective, and Orally Bioavailable Inverse Agonist of Retinoic Acid Receptor-Related Orphan Receptor C2.
J.Med.Chem., 64:13807-13829, 2021

PubMed Abstract: Inverse agonists of the nuclear receptor RORC2 have been widely pursued as a potential treatment for a variety of autoimmune diseases. We have discovered a novel series of isoindoline-based inverse agonists of the nuclear receptor RORC2, derived from our recently disclosed RORC2 inverse agonist . Extensive structure-activity relationship (SAR) studies resulted in AZD0284 (), which combined potent inhibition of IL-17A secretion from primary human T17 cells with excellent metabolic stability and good PK in preclinical species. In two preclinical studies, compound reduced thymocyte numbers in mice and showed dose-dependent reduction of IL-17A containing γδ-T cells and of IL-17A and IL-22 RNA in the imiquimod induced inflammation model. Based on these data and a favorable safety profile, was progressed to phase 1 clinical studies.

PubMed: 34464130
DOI: 10.1021/acs.jmedchem.1c01197

Experimental method

X-RAY DIFFRACTION (1.953 Å)