title: Synthesis and evaluation of Hsp90 inhibitors that contain the 1,4-naphthoquinone scaffold.
abstract: High-throughput screening of a library of diverse molecules has identified the 1,4-naphthoquinone scaffold as a new class of Hsp90 inhibitors. The synthesis and evaluation of a rationally-designed series of analogues containing the naphthoquinone core scaffold has provided key structure-activity relationships for these compounds. The most active inhibitors exhibited potent in vitro activity with low micromolar IC(50) values in anti-proliferation and Her2 degradation assays. In addition, 3g, 12, and 13a induced the degradation of oncogenic Hsp90 client proteins, a hallmark of Hsp90 inhibition. The identification of these naphthoquinones as Hsp90 inhibitors provides a new scaffold upon which improved Hsp90 inhibitors can be developed.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr., Malott 4070, Lawrence, KS 66045-7563, United States.
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Hill
authors.forename: Jason
authors.initials: J
authors.lastname: Davenport
authors.forename: Robert L
authors.initials: RL
authors.lastname: Matts
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D009285:Naphthoquinones; D018719:Erb-b2 Receptor Tyrosine Kinases; D054852:Small Molecule Libraries