8FB1

HUMAN RETENOID-RELATED ORPHAN RECEPTOR-GAMMA (RORC2) LIGAND-BINDING DOMAIN IN COMPLEX WITH COMPOUND 6a ANDINDAZOLE ACID BOUND IN H12-POCKET

8FB1 の概要

• エントリーDOI: 10.2210/pdb8fb1/pdb
• 分子名称: Nuclear receptor ROR-gamma, N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)-4-fluorobenzene-1-sulfonamide, 4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-4-fluoro-1H-indazol-3-yl}-3-fluorobenzoic acid, ... (4 entities in total)
• 機能のキーワード: rorc2, rorgammat, structure-based design, macrocyclization, topical delivery, dna binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62927.12

構造登録者

Vajdos, F.F. (登録日: 2022-11-29, 公開日: 2023-03-01, 最終更新日: 2024-11-13)

主引用文献

Schnute, M.E.,Trujillo, J.I.,Lee, K.L.,Unwalla, R.,Vajdos, F.F.,Kauppi, B.,Nuhant, P.,Flick, A.C.,Crouse, K.K.,Zhao, Y.,Samuel, A.,Lombardo, V.,Taylor, A.P.,Brault, A.L.,Knafels, J.D.,Vazquez, M.L.,Berstein, G.
Macrocyclic Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonists.
Acs Med.Chem.Lett., 14:191-198, 2023

PubMed Abstract: Macrocyclic retinoic acid receptor-related orphan receptor C2 (RORC2) inverse agonists have been designed with favorable properties for topical administration. Inspired by the unanticipated bound conformation of an acyclic sulfonamide-based RORC2 ligand from cocrystal structure analysis, macrocyclic linker connections between the halves of the molecule were explored. Further optimization of analogues was accomplished to maximize potency and refine physiochemical properties (MW, lipophilicity) best suited for topical application. Compound demonstrated potent inhibition of interleukin-17A (IL-17A) production by human Th17 cells and in vitro permeation through healthy human skin achieving high total compound concentration in both skin epidermis and dermis layers.

PubMed: 36793423
DOI: 10.1021/acsmedchemlett.2c00500

実験手法

X-RAY DIFFRACTION (2.18 Å)