title: Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.
abstract: Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.
authors.affiliation: Medicinal Chemistry, Astex Therapeutics, Ltd., Cambridge, UK. a.woodhead@astex-therapeutics.com
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Woodhead
authors.forename: Hayley
authors.initials: H
authors.lastname: Angove
authors.forename: Maria G
authors.initials: MG
authors.lastname: Carr
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Miles
authors.initials: M
authors.lastname: Congreve
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Coyle
authors.forename: Jose
authors.initials: J
authors.lastname: Cosme
authors.forename: Brent
authors.initials: B
authors.lastname: Graham
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Day
authors.forename: Robert
authors.initials: R
authors.lastname: Downham
authors.forename: Lynsey
authors.initials: L
authors.lastname: Fazal
authors.forename: Ruth
authors.initials: R
authors.lastname: Feltell
authors.forename: Eva
authors.initials: E
authors.lastname: Figueroa
authors.forename: Martyn
authors.initials: M
authors.lastname: Frederickson
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lewis
authors.forename: Rachel
authors.initials: R
authors.lastname: McMenamin
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: M Alistair
authors.initials: MA
authors.lastname: O'Brien
authors.forename: Lina
authors.initials: L
authors.lastname: Parra
authors.forename: Sahil
authors.initials: S
authors.lastname: Patel
authors.forename: Theresa
authors.initials: T
authors.lastname: Phillips
authors.forename: David C
authors.initials: DC
authors.lastname: Rees
authors.forename: Sharna
authors.initials: S
authors.lastname: Rich
authors.forename: Donna-Michelle
authors.initials: DM
authors.lastname: Smith
authors.forename: Gary
authors.initials: G
authors.lastname: Trewartha
authors.forename: Mladen
authors.initials: M
authors.lastname: Vinkovic
authors.forename: Brian
authors.initials: B
authors.lastname: Williams
authors.forename: Alison J-A
authors.initials: AJ
authors.lastname: Woolford
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D054833:Isoindoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D012995:Solubility; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; D008024:Ligands; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone