6DF6

Crystal structure of estrogen receptor alpha in complex with receptor degrader 16ab

6DF6 の概要

• エントリーDOI: 10.2210/pdb6df6/pdb
• 分子名称: Estrogen receptor, (8R)-8-(4-{2-[3-(fluoromethyl)azetidin-1-yl]ethoxy}phenyl)-1,8-dihydro-2H-[1]benzopyrano[4,3-d][1]benzoxepine-5,11-diol, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: era, antagonist, inverse agonist, receptor, breast cancer, degrader, ligand, estrogen receptor, nuclear protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 130063.51

構造登録者

Kiefer, J.R.,Vinogradova, M.,Liang, J.,Zhang, B.,Ortwine, D.F.,Nettles, K.W.,Nwachukwu, J.C. (登録日: 2018-05-14, 公開日: 2019-02-20, 最終更新日: 2024-03-13)

主引用文献

Zhang, B.,Kiefer, J.R.,Blake, R.A.,Chang, J.H.,Hartman, S.,Ingalla, E.R.,Kleinheinz, T.,Mody, V.,Nannini, M.,Ortwine, D.F.,Ran, Y.,Sambrone, A.,Sampath, D.,Vinogradova, M.,Zhong, Y.,Nwachukwu, J.C.,Nettles, K.W.,Lai, T.,Liao, J.,Zheng, X.,Chen, H.,Wang, X.,Liang, J.
Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha.
Bioorg. Med. Chem. Lett., 29:905-911, 2019

PubMed Abstract: Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+ breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays.

PubMed: 30732944
DOI: 10.1016/j.bmcl.2019.01.036

実験手法

X-RAY DIFFRACTION (2.5 Å)