Design, synthesis, and structure--activity relationships for chimeric inhibitors of Hsp90.
Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.
Shen
Gang
G
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045-7563, USA.
Wang
Mingwen
M
Welch
Timothy R
TR
Blagg
Brian S J
BS
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018942:Macrolides; D018832:Molecular Chaperones; C035359:monorden; C001277:geldanamycin