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

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• 作者：Maria Gabriella Brasca ; Sergio Mantegani ; Nadia Amboldi ; Simona Bindi ; Dannica Caronni ; Elena Casale ; Walter Ceccarelli ; Nicoletta Colombo ; Anna De Ponti ; Daniele Donati ; Antonella Ermoli ; Gabriele Fachin ; Eduard R. Felder ; Ronald D. Ferguson ; Claudio Fiorelli ; Marco Guanci ; Antonella Isacchi ; Enrico Pesenti ; Paolo Polucci ; Laura Riceputi ; et al.
• 关键词：Fragment based drug discovery ; Tumor cell proliferation inhibition ; Anti-cancer agents
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 November, 2013
• 年：2013
• 卷：21
• 期：22
• 页码：7047-7063
• 全文大小：3339 K

文摘

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.