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

Melanie Ann Rehder Silinski; KH Huang; TE Barta; JW Rice; ED Smith; AJ Ommen; W Ma; JM Veal; RP Fadden; AF Barabasz; BE Foley; PF Hughes; GJ Hanson; CJ Markworth; Melanie Ann Rehder Silinski; JM Partridge; PM Steed; SE Hall

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

Huang, KH., Barta, TE., Rice, JW., Smith, ED., Ommen, AJ., Ma, W., Veal, JM., Fadden, RP., Barabasz, AF., Foley, BE., Hughes, PF., Hanson, GJ., Markworth, CJ., Silinski, M., Partridge, JM., Steed, PM., & Hall, SE. (2012). Discovery of novel aminoquinazolin-7-yl 6,7-dihydro-indol-4-ones as potent, selective inhibitors of heat shock protein 90. Bioorganic and Medicinal Chemistry Letters, 22(7), 2550-2554. https://doi.org/10.1016/j.bmcl.2012.01.137

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Abstract

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.