8X7E
Crystal Structure of the mutant Human ROR gamma Ligand Binding Domain With JTE-151
Summary for 8X7E
| Entry DOI | 10.2210/pdb8x7e/pdb |
| Descriptor | Nuclear receptor ROR-gamma, Nuclear receptor corepressor 2, (4~{S})-6-[(2-chloranyl-4-methyl-phenyl)amino]-4-[4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]-1,2-oxazol-3-yl]-6-oxidanylidene-hexanoic acid, ... (4 entities in total) |
| Functional Keywords | nuclear receptor, nuclear protein-inhibitor complex, nuclear protein/inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 8 |
| Total formula weight | 131421.43 |
| Authors | Akai, S.,Nomura, A.,Yamaguchi, K.,Adachi, T. (deposition date: 2023-11-24, release date: 2024-11-27) |
| Primary citation | Maeba, T.,Hirata, K.,Kotoku, M.,Seki, N.,Maeda, K.,Hirashima, S.,Yamanaka, H.,Sakai, T.,Obika, S.,Hori, A.,Hara, Y.,Noji, S.,Suwa, Y.,Yokota, M.,Fujioka, S.,Yamaguchi, T.,Katsuda, Y.,Hata, T.,Miyagawa, N.,Arita, K.,Nomura, Y.,Taniguchi, T.,Asahina, K.,Aratsu, Y.,Naka, Y.,Adachi, T.,Nomura, A.,Akai, S.,Oshida, S.I.,Pai, S.,Crowe, P.,Bradley, E.,Steensma, R.,Tao, H.,Fenn, M.,Babine, R.,Li, X.,Thacher, S.,Soeta, T.,Ukaji, Y.,Shiozaki, M. Discovery and SAR of JTE-151: A Novel ROR gamma Inhibitor for Clinical Development. J.Med.Chem., 67:952-970, 2024 Cited by PubMed Abstract: A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial. PubMed: 38170624DOI: 10.1021/acs.jmedchem.3c01933 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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