title: N-aryl-benzimidazolones as novel small molecule HSP90 inhibitors.
abstract: We describe the development of a novel series of N-aryl-benzimidazolone HSP90 inhibitors (9) targeting the N-terminal ATP-ase site. SAR development was influenced by structure-based design based around X-ray structures of ligand bound HSP90 complexes. Lead compounds exhibited high binding affinities, ATP-ase inhibition and cellular client protein degradation.
authors.affiliation: Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. milan.bruncko@abbott.com
authors.forename: Milan
authors.initials: M
authors.lastname: Bruncko
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Huth
authors.forename: Sha
authors.initials: S
authors.lastname: Jin
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.forename: David J
authors.initials: DJ
authors.lastname: Madar
authors.forename: Chang H
authors.initials: CH
authors.lastname: Park
authors.forename: Cheol-Min
authors.initials: CM
authors.lastname: Park
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Petros
authors.forename: Christin
authors.initials: C
authors.lastname: Tse
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D018841:HSP90 Heat-Shock Proteins; C014353:benzimidazolone