6WOK
Crystal structure of estrogen receptor alpha in complex with receptor degrader 6
Summary for 6WOK
| Entry DOI | 10.2210/pdb6wok/pdb |
| Descriptor | Estrogen receptor, (2S)-3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-1-benzopyran-6-ol, (1R,3R)-1-(2,6-difluoro-4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline, ... (4 entities in total) |
| Functional Keywords | era, antagonist, inverse agonist, receptor, breast cancer, degrader, ligand, estrogen receptor, nuclear protein |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 130800.72 |
| Authors | Kiefer, J.R.,Vinogradova, M.,Liang, J.,Zhang, B.,Wang, X.,Labadie, S. (deposition date: 2020-04-24, release date: 2020-07-01, Last modification date: 2023-11-01) |
| Primary citation | Liang, J.,Blake, R.,Chang, J.,Friedman, L.S.,Goodacre, S.,Hartman, S.,Ingalla, E.R.,Kiefer, J.R.,Kleinheinz, T.,Labadie, S.,Li, J.,Lai, K.W.,Liao, J.,Mody, V.,McLean, N.,Metcalfe, C.,Nannini, M.,Otwine, D.,Ran, Y.,Ray, N.,Roussel, F.,Sambrone, A.,Sampath, D.,Vinogradova, M.,Wai, J.,Wang, T.,Yeap, K.,Young, A.,Zbieg, J.,Zhang, B.,Zheng, X.,Zhong, Y.,Wang, X. Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer. Acs Med.Chem.Lett., 11:1342-1347, 2020 Cited by PubMed Abstract: Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of that showed ionic interaction of azetidine with Asp351 residue. Importantly, showed favorable metabolic stability and good oral exposure. exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models. PubMed: 32551022DOI: 10.1021/acsmedchemlett.0c00224 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.309 Å) |
Structure validation
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