6BN6

IDENTIFICATION OF BICYCLIC HEXAFLUOROISOPROPYL ALCOHOL SULFONAMIDES AS RORGT/RORC INVERSE AGONISTS


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.204 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (ROR gamma /RORc) inverse agonists. Employing structure-based drug design to improve pregnane X receptor (PXR) selectivity.

Gong, H.Weinstein, D.S.Lu, Z.Duan, J.J.Stachura, S.Haque, L.Karmakar, A.Hemagiri, H.Raut, D.K.Gupta, A.K.Khan, J.Camac, D.Sack, J.S.Pudzianowski, A.Wu, D.R.Yarde, M.Shen, D.R.Borowski, V.Xie, J.H.Sun, H.D'Arienzo, C.Dabros, M.Galella, M.A.Wang, F.Weigelt, C.A.Zhao, Q.Foster, W.Somerville, J.E.Salter-Cid, L.M.Barrish, J.C.Carter, P.H.Dhar, T.G.M.

(2018) Bioorg Med Chem Lett 28: 85-93

  • DOI: https://doi.org/10.1016/j.bmcl.2017.12.006
  • Primary Citation of Related Structures:  
    6BN6, 6BNS

  • PubMed Abstract: 

    We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Y max in the PXR assay for long term preclinical pharmacokinetic (PK) studies.


  • Organizational Affiliation

    Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543-4000, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma
A, B
265Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
XGH BindingDB:  6BN6 EC50: min: 12, max: 31 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.204 
  • Space Group: P 61
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.76α = 90
b = 99.76β = 90
c = 126.55γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
SCALAdata scaling
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-12-20 
  • Deposition Author(s): Sack, J.

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-20
    Type: Initial release
  • Version 1.1: 2017-12-27
    Changes: Database references
  • Version 1.2: 2018-01-03
    Changes: Database references
  • Version 1.3: 2024-03-13
    Changes: Data collection, Database references