6CN5

HUMAN RETENOID-RELATED ORPHAN RECEPTOR-GAMMA LIGAND- BINDING DOMAIN IN COMPLEX WITH INDOLE LIGAND CP9b IN INVERSE AGONIST CONFORMATION


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist.

Schnute, M.E.Wennerstal, M.Alley, J.Bengtsson, M.Blinn, J.R.Bolten, C.W.Braden, T.Bonn, T.Carlsson, B.Caspers, N.Chen, M.Choi, C.Collis, L.P.Crouse, K.Farnegardh, M.Fennell, K.F.Fish, S.Flick, A.C.Goos-Nilsson, A.Gullberg, H.Harris, P.K.Heasley, S.E.Hegen, M.Hromockyj, A.E.Hu, X.Husman, B.Janosik, T.Jones, P.Kaila, N.Kallin, E.Kauppi, B.Kiefer, J.R.Knafels, J.Koehler, K.Kruger, L.Kurumbail, R.G.Kyne Jr., R.E.Li, W.Lofstedt, J.Long, S.A.Menard, C.A.Mente, S.Messing, D.Meyers, M.J.Napierata, L.Noteberg, D.Nuhant, P.Pelc, M.J.Prinsen, M.J.Rhonnstad, P.Backstrom-Rydin, E.Sandberg, J.Sandstrom, M.Shah, F.Sjoberg, M.Sundell, A.Taylor, A.P.Thorarensen, A.Trujillo, J.I.Trzupek, J.D.Unwalla, R.Vajdos, F.F.Weinberg, R.A.Wood, D.C.Xing, L.Zamaratski, E.Zapf, C.W.Zhao, Y.Wilhelmsson, A.Berstein, G.

(2018) J Med Chem 61: 10415-10439

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00392
  • Primary Citation of Related Structures:  
    6CN5, 6CN6

  • PubMed Abstract: 

    The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.


  • Organizational Affiliation

    Karo Bio AB (now Karo Pharma AB) , 111 48 Stockholm , Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma
A, B
262Homo sapiensMutation(s): 0 
Gene Names: RORCNR1F3RORGRZRG
UniProt & NIH Common Fund Data Resources
Find proteins for P51449 (Homo sapiens)
Explore P51449 
Go to UniProtKB:  P51449
PHAROS:  P51449
GTEx:  ENSG00000143365 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51449
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
F7M
Query on F7M

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
4-cyano-N-{3-[1-(cyclohexanecarbonyl)piperidin-4-yl]-1-methyl-1H-indol-5-yl}pyridine-2-carboxamide
C28 H31 N5 O2
LRJCIDHTWFKTMZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
F7M BindingDB:  6CN5 Ki: 20 (nM) from 1 assay(s)
IC50: min: 5, max: 120 (nM) from 3 assay(s)
Binding MOAD:  6CN5 Ki: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.173 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.663α = 90
b = 95.663β = 90
c = 135.897γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
autoPROCdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-09-05
    Type: Initial release
  • Version 1.1: 2018-09-19
    Changes: Data collection, Database references
  • Version 1.2: 2019-05-01
    Changes: Data collection, Database references
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description