Design of Dual Inhibitors of Histone Deacetylase 6 and Heat Shock Protein 90

[Image: see text] Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are widely investigated anticancer drug targets. Importantly, several lines of evidence indicate that their regulation and activity are intimately linked, and that their combined inhibition may lead to impressive therapeutic benefits. In this study, we developed and applied an integrated computational strategy to design dual inhibitors of HDAC6 and Hsp90. Although the two targets share very little homology, an integrated ligand-based and structure-based virtual screening approach indicated a subset of compounds possessing the key structural requirements for binding at both targets. In vitro tests demonstrated that some of the selected candidates are able to selectively inhibit HDAC6 over HDAC1, to increase the acetylation levels of tubulin on cell assays and to reduce cell proliferation. The discovered compounds represent valuable starting points for further hit optimization.