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

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.