7JTM

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(6T78-692) IN COMPLEX WITH A TRICYCLIC SULFONE RORGT INVERSE AGONIST

Summary for 7JTM

• Entry DOI: 10.2210/pdb7jtm/pdb
• Descriptor: Nuclear receptor ROR-gamma, trans-4-[(3aR,9bR)-8-cyano-9b-[(4-fluorophenyl)sulfonyl]-7-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-1,2,3a,4,5,9b-hexahydro-3H-benzo[e]indole-3-carbonyl]cyclohexane-1-carboxylic acid (3 entities in total)
• Functional Keywords: rorgt, nuclear hormone receptor, ligand-binding domain, inve agonist, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33565.51

Authors

Sack, J.S. (deposition date: 2020-08-18, release date: 2020-09-16, Last modification date: 2023-10-18)

Primary citation

Shi, Q.,Xiao, Z.,Yang, M.G.,Marcoux, D.,Cherney, R.J.,Yip, S.,Li, P.,Wu, D.R.,Weigelt, C.A.,Sack, J.,Khan, J.,Ruzanov, M.,Wang, J.,Yarde, M.,Ellen Cvijic, M.,Li, S.,Shuster, D.J.,Xie, J.,Sherry, T.,Obermeier, M.,Fura, A.,Stefanski, K.,Cornelius, G.,Chacko, S.,Shu, Y.Z.,Khandelwal, P.,Hynes Jr., J.,Tino, J.A.,Salter-Cid, L.,Denton, R.,Zhao, Q.,Dhar, T.G.M.
Tricyclic sulfones as potent, selective and efficacious ROR gamma t inverse agonists - Exploring C6 and C8 SAR using late-stage functionalization.
Bioorg.Med.Chem.Lett., 30:127521-127521, 2020

PubMed Abstract: In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.

PubMed: 32882417
DOI: 10.1016/j.bmcl.2020.127521

Experimental method

X-RAY DIFFRACTION (2.43 Å)