6DXK
Glucocorticoid Receptor in complex with Compound 11
Summary for 6DXK
| Entry DOI | 10.2210/pdb6dxk/pdb |
| Descriptor | 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) |
| Functional Keywords | signaling protein, nuclear hormone receptor, ligand complex, transcription |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 60277.96 |
| Authors | 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. (deposition date: 2018-06-29, release date: 2018-10-03, Last modification date: 2023-10-11) |
| Primary citation | 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 Cited by 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: 30091920DOI: 10.1021/acs.jmedchem.8b00743 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.05 Å) |
Structure validation
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