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: Richard I Feldman, Bob Mintzer, Daguang Zhu, James M Wu, Sandra L Biroc, Shendong Yuan, Kumar Emayan, Zheng Chang, Deborah Chen, Damian O Arnaiz, Judi Bryant, Xue Snow Ge, Marc Whitlow, Marc Adler, Mark A Polokoff, Wei-Wei Li, Mike Ferrer, Takashi Sato, Jian-Ming Gu, Jun Shen, Jih-Lie Tseng, Harald Dinter, Brad Buckman
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 74 Issue 1 Pg. 43-50 (Jul 2009) ISSN: 1747-0285 [Electronic] England
• PMID: 19519743 (Publication Type: Journal Article)

Chemical References

• BX-2819
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• Triazoles
• tanespimycin

Topics

• Animals
• Benzoquinones (chemistry, pharmacology)
• Cell Line, Tumor
• Computer Simulation
• Crystallography, X-Ray
• Drug Screening Assays, Antitumor
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, metabolism)
• HT29 Cells
• Humans
• Lactams, Macrocyclic (chemistry, pharmacology)
• Mice
• Mice, Nude
• Transplantation, Heterologous
• Triazoles (chemistry, pharmacology)
• Xenograft Model Antitumor Assays