4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer

Title4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer
Publication TypeJournal Article
Year of Publication2008
AuthorsBrough, PA, Aherne W, Barril X, Borgognoni J, Boxall K, Cansfield JE, Cheung KM, Collins I, Davies NG, Drysdale MJ, Dymock B, Eccles SA, Finch H, Fink A, Hayes A, Howes R, Hubbard RE, James K, Jordan AM, Lockie A, Martins V, Massey A, Matthews TP, McDonald E, Northfield CJ, Pearl LH, Prodromou C, Ray S, Raynaud FI, Roughley SD, Sharp SY, Surgenor A, Walmsley DL, Webb P, Wood M, Workman P, Wright L
JournalJournal of medicinal chemistry
Pagination196 - 218
Date Published2008/01/24/
KeywordsAnimals; Antineoplastic Agents/chemical synthesis/pharmacokinetics/pharmacology; Binding, Antitumor; Fluorescence Polarization; HSP90 Heat-Shock Proteins/antagonists & inhibitors/metabolism; Humans; Isoxazoles/chemical synthesis/pharmacokinetics/pharmacology; Mice; Mice, Competitive; Cell Line, Heterologous, Molecular; Neoplasm Transplantation; Resorcinols/chemical synthesis/pharmacokinetics/pharmacology; Structure-Activity Relationship; Transplantation, Nude; Models, Tumor; Cell Proliferation/drug effects; Crystallography, X-Ray; Drug Screening Assays
AbstractInhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.