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}

Summary for 3HHU

• Entry DOI: 10.2210/pdb3hhu/pdb
• Related: 1BYQ 1OSF 1UY6 1YC1 1YET 2BSM 2BTO 2BYI 2C2L 2CCT 2CCU
• Descriptor: 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)
• Functional Keywords: hsp90, atpase, chaperone, atp-binding, heat shock, nucleotide-binding, phosphorylation, alternative splicing, cytoplasm, phosphoprotein, stress response
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 2
• Total formula weight: 51249.80

Authors

Adler, M.,Whitlow, M. (deposition date: 2009-05-17, release date: 2009-07-14, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.59 Å)