title: Discovery of 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones as potent and selective Hsp90 inhibitors.
abstract: A new series of compounds, 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones, have been designed and identified as potent and selective inhibitors of Hsp90. These compounds demonstrated nanomolar potency toward both Hsp90-regulated Her2 degradation and the growth of a panel of human tumor cell lines in cell-based assays. High selectivity of these compounds toward Hsp90 was evident given that they did not inhibit a panel of 34 kinases at 10microM. The structure-activity relationship (SAR) of this series is reported here.
authors.affiliation: Poniard Pharmaceuticals, Inc., South San Francisco, CA 94080, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Li
authors.forename: Ellyn
authors.initials: E
authors.lastname: Shocron
authors.forename: Aimin
authors.initials: A
authors.lastname: Song
authors.forename: Neela
authors.initials: N
authors.lastname: Patel
authors.forename: Connie L
authors.initials: CL
authors.lastname: Sun
mesh_terms: D045744:Cell Line, Tumor; D003198:Computer Simulation; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011621:Pteridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011621:Pteridines