Potent Triazolothione Inhibitor of Heat-Shock Protein-90

被引：25

作者：

Feldman, Richard I. ^{[1
]}

Mintzer, Bob ^{[1
]}

Zhu, Daguang ^{[1
]}

Wu, James M. ^{[1
]}

Biroc, Sandra L. ^{[1
]}

Yuan, Shendong ^{[1
]}

Emayan, Kumar ^{[1
]}

Chang, Zheng ^{[1
]}

Chen, Deborah ^{[1
]}

Arnaiz, Damian O. ^{[1
]}

Bryant, Judi ^{[1
]}

Ge, Xue Snow ^{[1
]}

Whitlow, Marc ^{[1
]}

Adler, Marc ^{[1
]}

Polokoff, Mark A. ^{[1
]}

Li, Wei-Wei ^{[1
]}

Ferrer, Mike ^{[1
]}

Sato, Takashi ^{[1
]}

Gu, Jian-Ming ^{[1
]}

Shen, Jun ^{[1
]}

Tseng, Jih-Lie ^{[1
]}

Dinter, Harald ^{[1
]}

Buckman, Brad ^{[1
]}

机构：

[1] Bayer Healthcare, Richmond, CA 94804 USA

来源：

CHEMICAL BIOLOGY & DRUG DESIGN | 2009年 / 74卷 / 01期

关键词：

heat shock; Hsp90; inhibitor; small molecule; triazolothione; HSP90 MOLECULAR CHAPERONE; TUMOR SELECTIVITY; CRYSTAL-STRUCTURE; BREAST-CANCER; PHASE-I; HEAT-SHOCK-PROTEIN-90; RADICICOL; IDENTIFICATION; GELDANAMYCIN; DERIVATIVES;

D O I：

10.1111/j.1747-0285.2009.00833.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：43 / 50

页数：8

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