6DXK

Glucocorticoid Receptor in complex with Compound 11

6DXK の概要

• エントリーDOI: 10.2210/pdb6dxk/pdb
• 分子名称: Glucocorticoid receptor, (8S,11R,13S,14S,17S)-11-[4-(dimethylamino)phenyl]-17-(3,3-dimethylbut-1-yn-1-yl)-17-hydroxy-13-methyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one (non-preferred name) (3 entities in total)
• 機能のキーワード: signaling protein, nuclear hormone receptor, ligand complex, transcription
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60277.96

構造登録者

Rew, Y.,Du, X.,Eksterowicz, J.,Zhou, H.,Jahchan, N.,Zhu, L.,Yan, X.,Kawai, H.,McGee, L.R.,Medina, J.C.,Huang, T.,Chen, C.,Zavorotinskaya, T.,Sutimantanapi, D.,Waszczuk, J.,Jackson, E.,Huang, E.,Ye, Q.,Fantin, V.R.,Daqing, S. (登録日: 2018-06-29, 公開日: 2018-10-03, 最終更新日: 2023-10-11)

主引用文献

Rew, Y.,Du, X.,Eksterowicz, J.,Zhou, H.,Jahchan, N.,Zhu, L.,Yan, X.,Kawai, H.,McGee, L.R.,Medina, J.C.,Huang, T.,Chen, C.,Zavorotinskaya, T.,Sutimantanapi, D.,Waszczuk, J.,Jackson, E.,Huang, E.,Ye, Q.,Fantin, V.R.,Sun, D.
Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101).
J. Med. Chem., 61:7767-7784, 2018

PubMed Abstract: The glucocorticoid receptor (GR) has been linked to therapy resistance across a wide range of cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced androgen receptor (AR) agonistic activity amenable for dosing in androgen receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR OVCAR5 ovarian cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.

PubMed: 30091920
DOI: 10.1021/acs.jmedchem.8b00743

実験手法

X-RAY DIFFRACTION (3.05 Å)