2UWD

Inhibition of the HSP90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole, isoxazole amide analogs

2UWD の概要

• エントリーDOI: 10.2210/pdb2uwd/pdb
• 関連するPDBエントリー: 1BYQ 1OSF 1UY6 1UY7 1UY8 1UY9 1UYC 1UYD 1UYE 1UYF 1UYG 1UYH 1UYI 1UYK 1UYL 1YC1 1YC3 1YC4 1YER 1YES 1YET 2BSM 2BT0 2BUG 2BYH 2BYI 2BZ5 2C2L 2CCS 2CCT 2CCU 2CDD 2FWY 2FWZ
• 分子名称: HEAT SHOCK PROTEIN HSP 90-ALPHA, MAGNESIUM ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: chaperone, heat shock, atp-binding, phosphorylation, nucleotide-binding
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus : P07900
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27135.25

構造登録者

Sharp, S.Y.,Prodromou, C.,Boxall, K.,Powers, M.V.,Holmes, J.L.,Box, G.,Matthews, T.P.,Cheung, K.M.,Kalusa, A.,James, K.,Hayes, A.,Hardcastle, A.,Dymock, B.,Brough, P.A.,Barril, X.,Cansfield, J.E.,Wright, L.M.,Surgenor, A.,Foloppe, N.,Aherne, W.,Pearl, L.,Jones, K.,McDonald, E.,Raynaud, F.,Eccles, S.,Drysdale, M.,Workman, P. (登録日: 2007-03-20, 公開日: 2007-04-24, 最終更新日: 2023-12-13)

主引用文献

Sharp, S.Y.,Prodromou, C.,Boxall, K.,Powers, M.V.,Holmes, J.L.,Box, G.,Matthews, T.P.,Cheung, K.M.,Kalusa, A.,James, K.,Hayes, A.,Hardcastle, A.,Dymock, B.,Brough, P.A.,Barril, X.,Cansfield, J.E.,Wright, L.,Surgenor, A.,Foloppe, N.,Hubbard, R.E.,Aherne, W.,Pearl, L.,Jones, K.,McDonald, E.,Raynaud, F.,Eccles, S.,Drysdale, M.,Workman, P.
Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues.
Mol. Cancer Ther., 6:1198-1211, 2007

PubMed Abstract: Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors.

PubMed: 17431102
DOI: 10.1158/1535-7163.MCT-07-0149

実験手法

X-RAY DIFFRACTION (1.9 Å)