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

7JTM の概要

• エントリーDOI: 10.2210/pdb7jtm/pdb
• 分子名称: 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)
• 機能のキーワード: rorgt, nuclear hormone receptor, ligand-binding domain, inve agonist, transferase-transferase inhibitor complex, transferase, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33565.51

構造登録者

Sack, J.S. (登録日: 2020-08-18, 公開日: 2020-09-16, 最終更新日: 2023-10-18)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.43 Å)