8FAV

HUMAN RETENOID-RELATED ORPHAN RECEPTOR-GAMMA (RORC2) LIGAND-BINDING DOMAIN IN COMPLEX WITH COMPOUND 5 ANDINDAZOLE ACID BOUND IN H12-POCKET

Summary for 8FAV

• Entry DOI: 10.2210/pdb8fav/pdb
• Descriptor: Nuclear receptor ROR-gamma, 3-cyano-N-(3-{[(3S)-4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl]methyl}-5-fluoro-2-methylphenyl)benzamide, 4-{1-[2-chloro-6-(trifluoromethyl)benzoyl]-4-fluoro-1H-indazol-3-yl}-3-fluorobenzoic acid, ... (5 entities in total)
• Functional Keywords: rorc2, rorgammat, structure-based design, macrocyclization, topical delivery, dna binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 62484.35

Authors

Vajdos, F.F. (deposition date: 2022-11-28, release date: 2023-03-01, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)