Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90)

: The design of multi-target drugs acting simultaneously on multiple signalingpathways is a growing field in medicinal chemistry, especially for the treatment of complexdiseases, such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drugtarget involved in tumor cells transformation. Being an epigenetic enzyme at the interplay ofmany biological processes, HDAC6 has become an attractive target for polypharmacologystudies aimed at improving the therapeutic efficacy of anticancer drugs. For example, themolecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation,and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 andHsp90 promotes synergistic antitumor effects on different cancer cell lines, highlighting thepotential benefits of developing a single molecule endowed with multi-target activity. Thisreview will summarize the complex interplay between HDAC6 and Hsp90, providing alsouseful hints for multi-target drug design and discovery approaches in this field. To this end,crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewedin light of discussing binding pockets features and pharmacophore requirements and providinguseful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitorsobtained so far, mostly based on chimeric approaches, will be summarized and putinto context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared,and ligand- and structure-based strategies potentially useful for the development of smallmolecular weight dual inhibitors will be proposed and discussed.