6P9F

Crystal structure of RAR-related orphan receptor C (NHIS-RORGT(244-487)-L6-SRC1(678-692)) in complex with a phenyl (3-phenylpyrrolidin-3-yl)sulfone inhibitor

Summary for 6P9F

• Entry DOI: 10.2210/pdb6p9f/pdb
• Descriptor: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 chimera, trans-4-{(3R)-3-[(4-fluorophenyl)sulfonyl]-3-[4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]pyrrolidine-1-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 inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 67028.93

Authors

Sack, J. (deposition date: 2019-06-10, release date: 2019-07-17, Last modification date: 2023-10-11)

Primary citation

Lu, Z.,Duan, J.J.,Xiao, H.,Neels, J.,Wu, D.R.,Weigelt, C.A.,Sack, J.S.,Khan, J.,Ruzanov, M.,An, Y.,Yarde, M.,Karmakar, A.,Vishwakrishnan, S.,Baratam, V.,Shankarappa, H.,Vanteru, S.,Babu, V.,Basha, M.,Kumar Gupta, A.,Kumaravel, S.,Mathur, A.,Zhao, Q.,Salter-Cid, L.M.,Carter, P.H.,Murali Dhar, T.G.
Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as ROR gamma t inverse agonists.
Bioorg.Med.Chem.Lett., 29:2265-2269, 2019

PubMed Abstract: An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.

PubMed: 31257087
DOI: 10.1016/j.bmcl.2019.06.036

Experimental method

X-RAY DIFFRACTION (2.8 Å)