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Bioorg Med Chem. 2009 Jan 15;17(2):634-40. doi: 10.1016/j.bmc.2008.11.064. Epub 2008 Dec 3.

Synthesis and evaluation of Hsp90 inhibitors that contain the 1,4-naphthoquinone scaffold.

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Department of Medicinal Chemistry, The University of Kansas, 1251 Wescoe Hall Dr., Malott 4070, Lawrence, KS 66045-7563, United States.


High-throughput screening of a library of diverse molecules has identified the 1,4-naphthoquinone scaffold as a new class of Hsp90 inhibitors. The synthesis and evaluation of a rationally-designed series of analogues containing the naphthoquinone core scaffold has provided key structure-activity relationships for these compounds. The most active inhibitors exhibited potent in vitro activity with low micromolar IC(50) values in anti-proliferation and Her2 degradation assays. In addition, 3g, 12, and 13a induced the degradation of oncogenic Hsp90 client proteins, a hallmark of Hsp90 inhibition. The identification of these naphthoquinones as Hsp90 inhibitors provides a new scaffold upon which improved Hsp90 inhibitors can be developed.

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