6CN6

RORC2 LBD complexed with compound 34

6CN6 の概要

• エントリーDOI: 10.2210/pdb6cn6/pdb
• 分子名称: Nuclear receptor ROR-gamma, 3-cyano-N-{3-[1-(cyclopentanecarbonyl)piperidin-4-yl]-1,4-dimethyl-1H-indol-5-yl}benzamide (3 entities in total)
• 機能のキーワード: nuclear receptor, signaling protein
• 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: 30404.01

構造登録者

Kauppi, B.,Vajdos, F. (登録日: 2018-03-07, 公開日: 2018-09-05, 最終更新日: 2024-11-06)

主引用文献

Schnute, M.E.,Wennerstal, M.,Alley, J.,Bengtsson, M.,Blinn, J.R.,Bolten, C.W.,Braden, T.,Bonn, T.,Carlsson, B.,Caspers, N.,Chen, M.,Choi, C.,Collis, L.P.,Crouse, K.,Farnegardh, M.,Fennell, K.F.,Fish, S.,Flick, A.C.,Goos-Nilsson, A.,Gullberg, H.,Harris, P.K.,Heasley, S.E.,Hegen, M.,Hromockyj, A.E.,Hu, X.,Husman, B.,Janosik, T.,Jones, P.,Kaila, N.,Kallin, E.,Kauppi, B.,Kiefer, J.R.,Knafels, J.,Koehler, K.,Kruger, L.,Kurumbail, R.G.,Kyne Jr., R.E.,Li, W.,Lofstedt, J.,Long, S.A.,Menard, C.A.,Mente, S.,Messing, D.,Meyers, M.J.,Napierata, L.,Noteberg, D.,Nuhant, P.,Pelc, M.J.,Prinsen, M.J.,Rhonnstad, P.,Backstrom-Rydin, E.,Sandberg, J.,Sandstrom, M.,Shah, F.,Sjoberg, M.,Sundell, A.,Taylor, A.P.,Thorarensen, A.,Trujillo, J.I.,Trzupek, J.D.,Unwalla, R.,Vajdos, F.F.,Weinberg, R.A.,Wood, D.C.,Xing, L.,Zamaratski, E.,Zapf, C.W.,Zhao, Y.,Wilhelmsson, A.,Berstein, G.
Discovery of 3-Cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist.
J. Med. Chem., 61:10415-10439, 2018

PubMed Abstract: The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for RORC2, inhibition of IL-17 production in Th17 cells, and selectivity against the related RORA and RORB receptor isoforms. Lead optimization to improve the potency and metabolic stability of this hit focused on two key design strategies, namely, iterative optimization driven by increasing lipophilic efficiency and structure-guided conformational restriction to achieve optimal ground state energetics and maximize receptor residence time. This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.

PubMed: 30130103
DOI: 10.1021/acs.jmedchem.8b00392

実験手法

X-RAY DIFFRACTION (2.45 Å)