7KCO

ROR gamma in complex with SCR2 and compound 3

Summary for 7KCO

• Entry DOI: 10.2210/pdb7kco/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 62104.97

Authors

Durbin, J.D.,Guo, S.Y.,Stout, S.L.,Clawson, D.K. (deposition date: 2020-10-06, release date: 2021-04-21, Last modification date: 2024-04-03)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.86 Å)