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Potent Triazolothione Inhibitor of Heat-Shock Protein-90

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...

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Published in:Chemical biology & drug design 2009-07, Vol.74 (1), p.43-50
Main Authors: Feldman, Richard I, Mintzer, Bob, Zhu, Daguang, Wu, James M, Biroc, Sandra L, Yuan, Shendong, Emayan, Kumar, Chang, Zheng, Chen, Deborah, Arnaiz, Damian O, Bryant, Judi, Ge, Xue Snow, Whitlow, Marc, Adler, Marc, Polokoff, Mark A, Li, Wei-Wei, Ferrer, Mike, Sato, Takashi, Gu, Jian-Ming, Shen, Jun, Tseng, Jih-Lie, Dinter, Harald, Buckman, Brad
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Language:English
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Summary: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 n m (range of 7-72 n m). 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.
ISSN:1747-0277
1747-0285
DOI:10.1111/j.1747-0285.2009.00833.x