5AAU

Optimization of a novel binding motif to to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H- pyrido(3,4-b)indol-1-yl)phenyl)acrylic acid (AZD9496), a potent and orally bioavailable selective estrogen receptor downregulator and antagonist

5AAU の概要

• エントリーDOI: 10.2210/pdb5aau/pdb
• 関連するPDBエントリー: 5AAV
• 分子名称: ESTROGEN RECEPTOR, 3-(1-(4-Chlorophenyl)-3,4-dihydro-1H-pyrido(3,4-b)indol-2(9H)-yl)propanoic acid (3 entities in total)
• 機能のキーワード: signaling protein, breast cancer, estrogen receptor downregulator, fulvestrant, azd9496, nuclear hormone receptor
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 58052.83

構造登録者

Norman, R.A.,Bradbury, R.H.,de Almeida, C.,Andrews, D.M.,Ballard, P.,Buttar, D.,Callis, R.J.,Currie, G.S.,Curwen, J.O.,Davies, C.D.,de Savi, C.,Donald, C.S.,Feron, L.J.L.,Glossop, S.C.,Hayter, B.R.,Karoutchi, G.,Lamont, S.G.,MacFaul, P.,Moss, T.,Pearson, S.E.,Rabow, A.A.,Tonge, M.,Walker, G.E.,Weir, H.M.,Wilson, Z. (登録日: 2015-07-28, 公開日: 2015-10-14, 最終更新日: 2024-05-01)

主引用文献

De Savi, C.,Bradbury, R.H.,Rabow, A.A.,Norman, R.A.,De Almeida, C.,Andrews, D.M.,Ballard, P.,Buttar, D.,Callis, R.,Currie, G.S.,Davies, C.,Donald, C.,Feron, L.,Hayter, B.R.,Hussain, S.,Karoutchi, G.,Lamont, S.,Macfaul, P.A.,Moss, T.A.,Pearson, S.,Tonge, M.,Walker, G.,Weir, H.,Wilson, Z.
Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-Fluoro-2-Methylpropyl)-3-Methyl-2, 3,4,9-Tetrahydro-1H-Pyrido[3,4-B]Indol-1-Yl)Phenyl)Acrylic Acid (Azd9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist.
J.Med.Chem., 58:8128-, 2015

PubMed Abstract: The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.

PubMed: 26407012
DOI: 10.1021/ACS.JMEDCHEM.5B00984

実験手法

X-RAY DIFFRACTION (1.9 Å)