2. Academic Validation
  3. Potent triazolothione inhibitor of heat-shock protein-90

Potent triazolothione inhibitor of heat-shock protein-90

  • Chem Biol Drug Des. 2009 Jul;74(1):43-50. doi: 10.1111/j.1747-0285.2009.00833.x.
Richard I Feldman 1,  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
Affiliations

Affiliation

  • 1 Bayer Healthcare, 2600 Hilltop Drive, Richmond, CA 94804, USA. rick.feldman@bayer.com
PMID: 19519743 DOI: 10.1111/j.1747-0285.2009.00833.x
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157085
    Hsp90抑制剂
    HSP
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