6U25

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

6U25 の概要

• エントリーDOI: 10.2210/pdb6u25/pdb
• 分子名称: 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)
• 機能のキーワード: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33632.60

構造登録者

Sack, J. (登録日: 2019-08-19, 公開日: 2019-11-06, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.61 Å)