6U25

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

Summary for 6U25

• Entry DOI: 10.2210/pdb6u25/pdb
• Descriptor: NUCLEAR RECEPTOR COACTIVATOR 1 CHIMERA, trans-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]cyclohexane-1-carboxylic acid, GLYCEROL, ... (4 entities in total)
• Functional Keywords: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 33632.60

Authors

Sack, J. (deposition date: 2019-08-19, release date: 2019-11-06, Last modification date: 2023-10-11)

Primary citation

Marcoux, D.,Duan, J.J.,Shi, Q.,Cherney, R.J.,Srivastava, A.S.,Cornelius, L.,Batt, D.G.,Liu, Q.,Beaudoin-Bertrand, M.,Weigelt, C.A.,Khandelwal, P.,Vishwakrishnan, S.,Selvakumar, K.,Karmakar, A.,Gupta, A.K.,Basha, M.,Ramlingam, S.,Manjunath, N.,Vanteru, S.,Karmakar, S.,Maddala, N.,Vetrichelvan, M.,Gupta, A.,Rampulla, R.A.,Mathur, A.,Yip, S.,Li, P.,Wu, D.R.,Khan, J.,Ruzanov, M.,Sack, J.S.,Wang, J.,Yarde, M.,Cvijic, M.E.,Li, S.,Shuster, D.J.,Borowski, V.,Xie, J.H.,McIntyre, K.W.,Obermeier, M.T.,Fura, A.,Stefanski, K.,Cornelius, G.,Hynes Jr., J.,Tino, J.A.,Macor, J.E.,Salter-Cid, L.,Denton, R.,Zhao, Q.,Carter, P.H.,Dhar, T.G.M.
Rationally Designed, Conformationally Constrained Inverse Agonists of ROR gamma t-Identification of a Potent, Selective Series with Biologic-Like in Vivo Efficacy.
J.Med.Chem., 62:9931-9946, 2019

PubMed Abstract: RORγt is an important nuclear receptor that regulates the production of several pro-inflammatory cytokines such as IL-17 and IL-22. As a result, RORγt has been identified as a potential target for the treatment of various immunological disorders such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases. Structure and computer-assisted drug design led to the identification of a novel series of tricyclic RORγt inverse agonists with significantly improved in vitro activity in the reporter (Gal4) and human whole blood assays compared to our previous chemotype. Through careful structure activity relationship, several potent and selective RORγt inverse agonists have been identified. Pharmacokinetic studies allowed the identification of the lead molecule with a low peak-to-trough ratio. This molecule showed excellent activity in an IL-2/IL-23-induced mouse pharmacodynamic study and demonstrated biologic-like efficacy in an IL-23-induced preclinical model of psoriasis.

PubMed: 31638797
DOI: 10.1021/acs.jmedchem.9b01369

Experimental method

X-RAY DIFFRACTION (2.61 Å)