6VQF

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244- 487)-L6-SRC1(678-692)) IN COMPLEX WITH AN INVERSE AGONIST

Summary for 6VQF

• Entry DOI: 10.2210/pdb6vqf/pdb
• Descriptor: Nuclear receptor ROR-gamma, (1R,3S,4R)-4-[(3aR,9bR)-9b-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonyl]-3-methylcyclohexane-1-carboxylic acid, GLYCEROL, ... (4 entities in total)
• Functional Keywords: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, transcription
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33646.62

Authors

Sack, J.S. (deposition date: 2020-02-05, release date: 2020-04-08, Last modification date: 2023-10-11)

Primary citation

Cherney, R.J.,Cornelius, L.A.M.,Srivastava, A.,Weigelt, C.A.,Marcoux, D.,Duan, J.J.,Shi, Q.,Batt, D.G.,Liu, Q.,Yip, S.,Wu, D.R.,Ruzanov, M.,Sack, J.,Khan, J.,Wang, J.,Yarde, M.,Cvijic, M.E.,Mathur, A.,Li, S.,Shuster, D.,Khandelwal, P.,Borowski, V.,Xie, J.,Obermeier, M.,Fura, A.,Stefanski, K.,Cornelius, G.,Tino, J.A.,Macor, J.E.,Salter-Cid, L.,Denton, R.,Zhao, Q.,Carter, P.H.,Dhar, T.G.M.
Discovery of BMS-986251: A Clinically Viable, Potent, and Selective ROR gamma t Inverse Agonist.
Acs Med.Chem.Lett., 11:1221-1227, 2020

PubMed Abstract: Novel tricyclic analogues were designed, synthesized, and evaluated as RORγt inverse agonists. Several of these compounds were potent in an IL-17 human whole blood assay and exhibited excellent oral bioavailability in mouse pharmacokinetic studies. This led to the identification of compound , which displayed dose-dependent inhibition of IL-17F production in a mouse IL-2/IL-23 stimulated pharmacodynamic model. In addition, compound was studied in mouse acanthosis and imiquimod-induced models of skin inflammation, where it demonstrated robust efficacy comparable to a positive control. As a result of this excellent overall profile, compound (BMS-986251) was selected as a clinically viable developmental candidate.

PubMed: 32551004
DOI: 10.1021/acsmedchemlett.0c00063

Experimental method

X-RAY DIFFRACTION (2 Å)