title: Discovery of novel aminoquinazolin-7-yl 6,7-dihydro-indol-4-ones as potent, selective inhibitors of heat shock protein 90.
abstract: A novel class of Hsp90 inhibitors, structurally distinct from previously reported scaffolds, was developed from rational design and optimization of a compound library screen hit. These aminoquinazoline derivatives, represented by compound 15 (SNX-6833) or 1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one, selectively bind to Hsp90 and inhibit its cellular activities at concentrations as low as single digit nanomolar.
authors.affiliation: Serenex Inc., 323 Foster Street, Durham, NC 27701, USA. khuang@pamlicopharma.com
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Huang
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Barta
authors.forename: John W
authors.initials: JW
authors.lastname: Rice
authors.forename: Emilie D
authors.initials: ED
authors.lastname: Smith
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Ommen
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.forename: James M
authors.initials: JM
authors.lastname: Veal
authors.forename: R Patrick
authors.initials: RP
authors.lastname: Fadden
authors.forename: Amy F
authors.initials: AF
authors.lastname: Barabasz
authors.forename: Briana E
authors.initials: BE
authors.lastname: Foley
authors.forename: Philip F
authors.initials: PF
authors.lastname: Hughes
authors.forename: Gunnar J
authors.initials: GJ
authors.lastname: Hanson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Markworth
authors.forename: Melanie
authors.initials: M
authors.lastname: Silinski
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Partridge
authors.forename: Paul M
authors.initials: PM
authors.lastname: Steed
authors.forename: Steven E
authors.initials: SE
authors.lastname: Hall
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D011799:Quinazolines; D054852:Small Molecule Libraries