6ZOR

Oestrogen receptor ligand binding domain in complex with compound 28

6ZOR の概要

• エントリーDOI: 10.2210/pdb6zor/pdb
• 分子名称: Estrogen receptor, 6-[(6~{S},8~{R})-8-methyl-7-[2,2,2-tris(fluoranyl)ethyl]-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]-~{N}-(1-propylazetidin-3-yl)pyridin-3-amine (3 entities in total)
• 機能のキーワード: oestrogen receptor, gene regulation
• 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: 58228.09

構造登録者

Breed, J. (登録日: 2020-07-07, 公開日: 2021-01-20, 最終更新日: 2024-01-31)

主引用文献

Scott, J.S.,Moss, T.A.,Balazs, A.,Barlaam, B.,Breed, J.,Carbajo, R.J.,Chiarparin, E.,Davey, P.R.J.,Delpuech, O.,Fawell, S.,Fisher, D.I.,Gagrica, S.,Gangl, E.T.,Grebe, T.,Greenwood, R.D.,Hande, S.,Hatoum-Mokdad, H.,Herlihy, K.,Hughes, S.,Hunt, T.A.,Huynh, H.,Janbon, S.L.M.,Johnson, T.,Kavanagh, S.,Klinowska, T.,Lawson, M.,Lister, A.S.,Marden, S.,McGinnity, D.F.,Morrow, C.J.,Nissink, J.W.M.,O'Donovan, D.H.,Peng, B.,Polanski, R.,Stead, D.S.,Stokes, S.,Thakur, K.,Throner, S.R.,Tucker, M.J.,Varnes, J.,Wang, H.,Wilson, D.M.,Wu, D.,Wu, Y.,Yang, B.,Yang, W.
Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist.
J.Med.Chem., 63:14530-14559, 2020

PubMed Abstract: Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of -[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6,8)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3-pyrazolo[4,3-]isoquinolin-6-yl]pyridin-3-amine (). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

PubMed: 32910656
DOI: 10.1021/acs.jmedchem.0c01163

実験手法

X-RAY DIFFRACTION (1.97 Å)