5AAV

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

Summary for 5AAV

• Entry DOI: 10.2210/pdb5aav/pdb
• Related: 5AAU
• Descriptor: ESTROGEN RECEPTOR, (2E)-3-{4-[(1E)-1,2-DIPHENYLBUT-1-ENYL]PHENYL}ACRYLIC ACID, ... (4 entities in total)
• Functional Keywords: signaling protein, breast cancer, estrogen receptor downregulator, fulvestrant, azd9496, nuclear hormone receptor
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Isoform 1: Nucleus . Isoform 3: Nucleus. Nucleus: P03372 P03372
• Total number of polymer chains: 2
• Total formula weight: 58001.88

Authors

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. (deposition date: 2015-07-29, release date: 2015-10-14, Last modification date: 2024-05-01)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.95 Å)