6CVH

Identification and biological evaluation of thiazole-based inverse agonists of RORgt

Summary for 6CVH

• Entry DOI: 10.2210/pdb6cvh/pdb
• Descriptor: Nuclear receptor ROR-gamma, trans-3-({4-(cyclohexylmethyl)-5-[3-(1-methylcyclopropyl)-5-{[(2R)-1,1,1-trifluoropropan-2-yl]carbamoyl}phenyl]-1,3-thiazole-2-carbonyl}amino)cyclobutane-1-carboxylic acid (2 entities in total)
• Functional Keywords: nuclear receptor rorgt, nuclear protein
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : P51449
• Total number of polymer chains: 1
• Total formula weight: 27027.29

Authors

Spurlino, J.,Milligan, C. (deposition date: 2018-03-28, release date: 2018-04-25, Last modification date: 2024-03-13)

Primary citation

Gege, C.,Cummings, M.D.,Albers, M.,Kinzel, O.,Kleymann, G.,Schluter, T.,Steeneck, C.,Nelen, M.I.,Milligan, C.,Spurlino, J.,Xue, X.,Leonard, K.,Edwards, J.P.,Fourie, A.,Goldberg, S.D.,Hoffmann, T.
Identification and biological evaluation of thiazole-based inverse agonists of ROR gamma t.
Bioorg. Med. Chem. Lett., 28:1446-1455, 2018

PubMed Abstract: The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORγt) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORγt lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORγt drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORγt inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORγt inhibition with this series.

PubMed: 29631962
DOI: 10.1016/j.bmcl.2018.03.093

Experimental method

X-RAY DIFFRACTION (3.5 Å)