6q7a

From Proteopedia

RORCVAR2 (RORGT, 264-499) IN COMPLEX WITH COMPOUND 4 AT 2.2A: Identification of N-aryl imidazoles as potent and selective RORgt inhibitors

Structural highlights

6q7a is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.2Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.

Publication Abstract from PubMed

RORgammat is considered the master transcription factor for the development of Th17 cells that produce pro-inflammatory cytokines such as IL-17A. Overproportionate Th17 cell abundance is associated with the pathogenesis of many inflammatory conditions including psoriasis. In a high-throughput FRET screen, we identified compound 1 as hit with promising lipE. Using structure-based drug design based on a number of X-ray co-crystal structures, we morphed this hit class into potent imidazoles, exemplified by compound 3. To improve the poor ADME properties of neutral imidazoles, we extended our ligands with carboxylic acid substituents towards 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 RORgammat 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.

Structure-based and property-driven optimization of N-aryl imidazoles towards potent and selective oral RORgammat inhibitors.,Hoegenauer K, Kallen J, Jimenez-Nunez E, Strang R, Ertl P, Cooke NG, Hintermann S, Voegtle M, Betschart C, Mckay DJJ, Wagner J, Ottl J, Beerli C, Billich A, Dawson J, Kaupmann K, Streiff M, Gobeau N, Harlfinger S, Stringer R, Guntermann C J Med Chem. 2019 Nov 15. doi: 10.1021/acs.jmedchem.9b01291. PMID:31729873^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Hoegenauer K, Kallen J, Jimenez-Nunez E, Strang R, Ertl P, Cooke NG, Hintermann S, Voegtle M, Betschart C, Mckay DJJ, Wagner J, Ottl J, Beerli C, Billich A, Dawson J, Kaupmann K, Streiff M, Gobeau N, Harlfinger S, Stringer R, Guntermann C. Structure-based and property-driven optimization of N-aryl imidazoles towards potent and selective oral RORgammat inhibitors. J Med Chem. 2019 Nov 15. doi: 10.1021/acs.jmedchem.9b01291. PMID:31729873 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01291