3HHU

Human heat-shock protein 90 (HSP90) in complex with {4-[3-(2,4-dihydroxy-5-isopropyl-phenyl)-5-thioxo- 1,5-dihydro-[1,2,4]triazol-4-yl]-benzyl}-carbamic acid ethyl ester {ZK 2819}

3HHU の概要

• エントリーDOI: 10.2210/pdb3hhu/pdb
• 関連するPDBエントリー: 1BYQ 1OSF 1UY6 1YC1 1YET 2BSM 2BTO 2BYI 2C2L 2CCT 2CCU
• 分子名称: Heat shock protein HSP 90-alpha, ethyl (4-{3-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-5-sulfanyl-4H-1,2,4-triazol-4-yl}benzyl)carbamate (3 entities in total)
• 機能のキーワード: hsp90, atpase, chaperone, atp-binding, heat shock, nucleotide-binding, phosphorylation, alternative splicing, cytoplasm, phosphoprotein, stress response
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm : P07900
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51249.80

構造登録者

Adler, M.,Whitlow, M. (登録日: 2009-05-17, 公開日: 2009-07-14, 最終更新日: 2024-02-21)

主引用文献

Feldman, R.I.,Mintzer, B.,Zhu, D.,Wu, J.M.,Biroc, S.L.,Yuan, S.,Emayan, K.,Chang, Z.,Chen, D.,Arnaiz, D.O.,Bryant, J.,Ge, X.S.,Whitlow, M.,Adler, M.,Polokoff, M.A.,Li, W.W.,Ferrer, M.,Sato, T.,Gu, J.M.,Shen, J.,Tseng, J.L.,Dinter, H.,Buckman, B.
Potent triazolothione inhibitor of heat-shock protein-90.
Chem.Biol.Drug Des., 74:43-50, 2009

PubMed 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.

PubMed: 19519743
DOI: 10.1111/j.1747-0285.2009.00833.x

実験手法

X-RAY DIFFRACTION (1.59 Å)