Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)

被引：32

作者：

Brasca, Maria Gabriella ^{[1
]}

Mantegani, Sergio ^{[1
]}

Amboldi, Nadia ^{[1
]}

Bindi, Simona ^{[1
]}

Caronni, Dannica ^{[1
]}

Casale, Elena ^{[1
]}

Ceccarelli, Walter ^{[1
]}

Colombo, Nicoletta ^{[1
]}

De Ponti, Anna ^{[1
]}

Donati, Daniele ^{[1
]}

Ermoli, Antonella ^{[1
]}

Fachin, Gabriele ^{[1
]}

Felder, Eduard R. ^{[1
]}

Ferguson, Ronald D. ^{[1
]}

Fiorelli, Claudio ^{[1
]}

Guanci, Marco ^{[1
]}

Isacchi, Antonella ^{[1
]}

Pesenti, Enrico ^{[1
]}

Polucci, Paolo ^{[1
]}

Riceputi, Laura ^{[1
]}

Sola, Francesco ^{[1
]}

Visco, Carlo ^{[1
]}

Zuccotto, Fabio ^{[1
]}

Fogliatto, Gianpaolo ^{[1
]}

机构：

[1] Nerviano Med Sci Srl, Oncol, I-20014 Nerviano, MI, Italy

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 22期

关键词：

Fragment based drug discovery; Tumor cell proliferation inhibition; Anti-cancer agents; MOLECULAR CHAPERONE HSP90; ANTITUMOR ACTIVITIES; EXHIBITS POTENT; HEAT-SHOCK-PROTEIN-90; AGENTS; GELDANAMYCIN; DERIVATIVES; GENERATION; MECHANISM; BINDING;

D O I：

10.1016/j.bmc.2013.09.018

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：

Novel small molecule inhibitors of heat shock protein 90 (Hsp90) were discovered with the help of a fragment based drug discovery approach (FBDD) and subsequent optimization with a combination of structure guided design, parallel synthesis and application of medicinal chemistry principles. These efforts led to the identification of compound 18 (NMS-E973), which displayed significant efficacy in a human ovarian A2780 xenograft tumor model, with a mechanism of action confirmed in vivo by typical modulation of known Hsp90 client proteins, and with a favorable pharmacokinetic and safety profile. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：7047 / 7063

页数：17

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