7KCO

ROR gamma in complex with SCR2 and compound 3

7KCO の概要

• エントリーDOI: 10.2210/pdb7kco/pdb
• 分子名称: Nuclear receptor ROR-gamma, Peptide GLU-LYS-HIS-LYS-ILE-LEU-HIS-ARG-LEU-LEU-GLN-ASP-SER, 1-[(2-chlorophenyl)methyl]-N-{[4-(methylsulfonyl)phenyl]methyl}-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-carboxamide, ... (5 entities in total)
• 機能のキーワード: inhibitor, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 62104.97

構造登録者

Durbin, J.D.,Guo, S.Y.,Stout, S.L.,Clawson, D.K. (登録日: 2020-10-06, 公開日: 2021-04-21, 最終更新日: 2024-04-03)

主引用文献

Lugar, C.W.,Clarke, C.A.,Morphy, R.,Rudyk, H.,Sapmaz, S.,Stites, R.E.,Vaught, G.M.,Furness, K.,Broughton, H.B.,Durst, G.L.,Clawson, D.K.,Stout, S.L.,Guo, S.Y.,Durbin, J.D.,Stayrook, K.R.,Edmondson, D.D.,Kikly, K.,New, N.E.,Bina, H.A.,Chambers, M.G.,Shetler, P.,Chang, W.Y.,Chang, V.C.,Barr, R.,Gough, W.H.,Steele, J.P.,Getman, B.,Patel, N.,Mathes, B.M.,Richardson, T.I.
Defining Target Engagement Required for Efficacy In Vivo at the Retinoic Acid Receptor-Related Orphan Receptor C2 (ROR gamma t).
J.Med.Chem., 64:5470-5484, 2021

PubMed Abstract: The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy . Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound , which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.

PubMed: 33852312
DOI: 10.1021/acs.jmedchem.0c01918

実験手法

X-RAY DIFFRACTION (1.86 Å)