6EL6

Glucocorticoid Receptor in complex with compound 4

6EL6 の概要

• エントリーDOI: 10.2210/pdb6el6/pdb
• 分子名称: Glucocorticoid receptor, Nuclear receptor coactivator 2, 1,2-ETHANEDIOL, ... (5 entities in total)
• 機能のキーワード: glucocorticoid receptor, nuclear hormone receptor, steroid receptor, ligand complex, peptide complex, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Isoform Alpha: Cytoplasm . Isoform Beta: Nucleus . Isoform Alpha-B: Nucleus : P04150; Nucleus: Q15596
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 34418.64

構造登録者

Edman, K.,Wissler, L. (登録日: 2017-09-28, 公開日: 2018-02-21, 最終更新日: 2024-01-17)

主引用文献

Ripa, L.,Edman, K.,Dearman, M.,Edenro, G.,Hendrickx, R.,Ullah, V.,Chang, H.F.,Lepisto, M.,Chapman, D.,Geschwindner, S.,Wissler, L.,Svanberg, P.,Lawitz, K.,Malmberg, J.,Nikitidis, A.,Olsson, R.I.,Bird, J.,Llinas, A.,Hegelund-Myrback, T.,Berger, M.,Thorne, P.,Harrison, R.,Kohler, C.,Drmota, T.
Discovery of a Novel Oral Glucocorticoid Receptor Modulator (AZD9567) with Improved Side Effect Profile.
J. Med. Chem., 61:1785-1799, 2018

PubMed Abstract: Synthetic glucocorticoids (GC) are essential for the treatment of a broad range of inflammatory diseases. However, their use is limited by target related adverse effects on, e.g., glucose homeostasis and bone metabolism. Starting from a nonsteroidal GR ligand (4) that is a full agonist in reporter gene assays, we exploited key functional triggers within the receptor, generating a range of structurally diverse partial agonists. Of these, only a narrow subset exhibited full anti-inflammatory efficacy and a significantly reduced impact on adverse effect markers in human cell assays compared to prednisolone. This led to the discovery of AZD9567 (15) with excellent in vivo efficacy when dosed orally in a rat model of joint inflammation. Compound 15 is currently being evaluated in clinical trials comparing the efficacy and side effect markers with those of prednisolone.

PubMed: 29424542
DOI: 10.1021/acs.jmedchem.7b01690

実験手法

X-RAY DIFFRACTION (2.4 Å)