title: Potent triazolothione inhibitor of heat-shock protein-90.
abstract: Heat-shock protein-90 is an attractive target for anticancer drugs, as heat-shock protein-90 blockers such as the ansamycin 17-(allylamino)-17-demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17-(allylamino)-17-demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template-related drawbacks. In this paper, we describe a new, potent non-ansamycin small-molecule inhibitor of heat-shock protein-90, BX-2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX-2819 to the ADP/ATP-binding pocket of heat-shock protein-90. The compound blocked expression of heat-shock protein-90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17-(allylamino)-17-demethoxygeldanamycin. In a panel of four cancer cell lines, BX-2819 blocked growth with an average IC(50) value of 32 nM (range of 7-72 nM). Efficacy studies demonstrated that treatment with BX-2819 significantly inhibited the growth of NCI-N87 and HT-29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat-shock protein-90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX-2819 and related analogs for the treatment of cancer.
authors.affiliation: Bayer Healthcare, 2600 Hilltop Drive, Richmond, CA 94804, USA. rick.feldman@bayer.com
authors.forename: Richard I
authors.initials: RI
authors.lastname: Feldman
authors.forename: Bob
authors.initials: B
authors.lastname: Mintzer
authors.forename: Daguang
authors.initials: D
authors.lastname: Zhu
authors.forename: James M
authors.initials: JM
authors.lastname: Wu
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Biroc
authors.forename: Shendong
authors.initials: S
authors.lastname: Yuan
authors.forename: Kumar
authors.initials: K
authors.lastname: Emayan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chang
authors.forename: Deborah
authors.initials: D
authors.lastname: Chen
authors.forename: Damian O
authors.initials: DO
authors.lastname: Arnaiz
authors.forename: Judi
authors.initials: J
authors.lastname: Bryant
authors.forename: Xue Snow
authors.initials: XS
authors.lastname: Ge
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Mark A
authors.initials: MA
authors.lastname: Polokoff
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.forename: Mike
authors.initials: M
authors.lastname: Ferrer
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Gu
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Jih-Lie
authors.initials: JL
authors.lastname: Tseng
authors.forename: Harald
authors.initials: H
authors.lastname: Dinter
authors.forename: Brad
authors.initials: B
authors.lastname: Buckman
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C543002:BX-2819; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D014230:Triazoles; C112765:tanespimycin