PDBsum entry 6q7h

Transcription

PDB id: 6q7h

Contents

Protein chain

225 a.a.

Ligands

HL8 ×2

Waters ×80

PDB id:

6q7h

Name:

Transcription

Title:

Rorcvar2 (rorgt, 264-499) in complex with compound 9 at 2.3a: identification of n-aryl imidazoles as potent and selective rorgt inhibitors

Structure:

Nuclear receptor ror-gamma. Chain: a. Fragment: c-terminal domain, ligand binding domain. Synonym: nuclear receptor rzr-gamma,nuclear receptor subfamily 1 group f member 3,rar-related orphan receptor c,retinoid-related orphan receptor-gamma. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: rorc, nr1f3, rorg, rzrg. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

2.30Å R-factor: 0.234 R-free: 0.249

Authors:

J.Kallen

Key ref:

K.Hoegenauer et al. (2019). Structure-Based and Property-Driven Optimization of N-Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors. J Med Chem, 62, 10816-10832. PubMed id: 31729873 DOI: 10.1021/acs.jmedchem.9b01291

Date:

13-Dec-18 Release date: 27-Nov-19

Protein chain

P51449  (RORG_HUMAN) -  Nuclear receptor ROR-gamma from Homo sapiens

Seq: 518 a.a.

Struc: 225 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1021/acs.jmedchem.9b01291

J Med Chem 62:10816-10832 (2019)

PubMed id: 31729873

Structure-Based and Property-Driven Optimization of N-Aryl Imidazoles toward Potent and Selective Oral RORγt Inhibitors.

K.Hoegenauer, J.Kallen, E.Jiménez-Núñez, R.Strang, P.Ertl, N.G.Cooke, S.Hintermann, M.Voegtle, C.Betschart, D.J.J.McKay, J.Wagner, J.Ottl, C.Beerli, A.Billich, J.Dawson, K.Kaupmann, M.Streiff, N.Gobeau, S.Harlfinger, R.Stringer, C.Guntermann.

ABSTRACT

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) is considered to be the master transcription factor for the development of Th17 cells that produce proinflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput fluorescence resonance energy transfer (FRET) screen, we identified compound 1 as a hit with promising lipophilic efficiency (LipE). Using structure-based drug design based on a number of X-ray cocrystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor absorption, distribution, metabolism, and excretion (ADME) properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents toward a polar, water-rich area of the protein. This highly lipophilicity-efficient modification ultimately led to the discovery of compound 14, a potent and selective inhibitor of RORγt with good ADME properties and excellent in vivo pharmacokinetics. This compound showed good efficacy in an in vivo delayed-type hypersensitivity pharmacology model in rats.