Discovery of novel aminoquinazolin-7-yl 6,7-dihydro-indol-4-ones as potent, selective inhibitors of heat shock protein 90

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• 作者：Kenneth H. Huang^&dagger ; ; ^{khuang@pamlicopharma.com} ; Thomas E. Barta ; John W. Rice ; Emilie D. Smith ; Andy J. Ommen ; Wei Ma ; James M. Veal ; R. Patrick Fadden ; Amy F. Barabasz ; Briana E. Foley ; Philip F. Hughes ; Gunnar J. Hanson ; Christopher J. Markworth ; Melanie Silinski ; Jeffrey M. Partridge ; Paul M. Steed ; Steven E. Hall
• 关键词：Hsp90 ; Chaperone ; Inhibitors ; Indolone ; Aminoquinazoline ; Quinazoline ; Her2 ; Cancer
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 April, 2012
• 卷：22
• 期：7
• 页码：2550-2554
• 文件大小：746 K

摘要

A novel class of Hsp90 inhibitors, structurally distinct from previously reported scaffolds, was developed from rational design and optimization of a compound library screen hit. These aminoquinazoline derivatives, represented by compound 15 (SNX-6833) or 1-(2-amino-4-methylquinazolin-7-yl)-3,6,6-trimethyl-6,7-dihydro-1H-indol-4(5H)-one, selectively bind to Hsp90 and inhibit its cellular activities at concentrations as low as single digit nanomolar.