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- Title
Potent Triazolothione Inhibitor of Heat-Shock Protein-90.
- Authors
Feldman, Richard I.; Mintzer, Bob; Daguang Zhu; Wu, James M.; Biroc, Sandra L.; Shendong Yuan; Emayan, Kumar; Zheng Chang; Chen, Deborah; Arnaiz, Damian O.; Bryant, Judi; Xue Snow Ge; Whitlow, Marc; Adler, Marc; Polokoff, Mark A.; Wei-Wei Li; Ferrer, Mike; Sato, Takashi; Jian-Ming Gu; Jun Shen
- 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 IC50 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.
- Subjects
HEAT shock proteins; ANTINEOPLASTIC agents; CANCER chemotherapy; CELLULAR pathology; TUMORS
- Publication
Chemical Biology & Drug Design, 2009, Vol 74, Issue 1, p43
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/j.1747-0285.2009.00833.x