7KXD

CRYSTAL STRUCTURE OF RAR-RELATED ORPHAN RECEPTOR C (NHIS-RORGT(244-487)-L6-SRC1(678-692)) IN COMPLEX WITH {3,5-DICHLORO-4-[4-METHOXY-3-(PROPAN-2-YL)PHENOXY]PHENYL}METHANOL

Summary for 7KXD

• Entry DOI: 10.2210/pdb7kxd/pdb
• Descriptor: Nuclear receptor ROR-gamma, Nuclear receptor coactivator 1 peptide chimera, {3,5-dichloro-4-[4-methoxy-3-(propan-2-yl)phenoxy]phenyl}methanol (3 entities in total)
• Functional Keywords: rorgt, nuclear hormone receptor, ligand-binding domain, inverse agonist, transferase-agonist complex, transferase/agonist
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 33228.15

Authors

Sack, J. (deposition date: 2020-12-03, release date: 2021-01-20, Last modification date: 2023-10-18)

Primary citation

Ruan, Z.,Park, P.K.,Wei, D.,Purandare, A.,Wan, H.,O'Malley, D.,Stachura, S.,Perez, H.,Cavallaro, C.L.,Weigelt, C.A.,Sack, J.S.,Ruzanov, M.,Khan, J.,Gururajan, M.,Wong, J.J.,Huang, Y.,Yarde, M.,Li, Z.,Chen, C.,Sun, H.,Borowski, V.,Xie, J.H.,Anthony, M.,Agler, M.,Fink, B.E.,Harikrishnan, L.S.
Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-gamma t (ROR gamma t) agonists.
Bioorg.Med.Chem.Lett., 35:127778-127778, 2021

PubMed Abstract: The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

PubMed: 33422603
DOI: 10.1016/j.bmcl.2021.127778

Experimental method

X-RAY DIFFRACTION (1.624 Å)