HDAC6 is an enzyme with a wide variety of substrates and interaction partners, which makes it an important regulator of diverse cellular processes and, in case of aberrant function, an actor in several diseases including cancer, neurodegenerative disorders and inflammation. Therefore, inhibitors have been developed to selectively target HDAC6. However, these compounds only target the deacetylase catalytic cavity, while also a ubiquitin binding domain (ZUB) is present, which enables HDAC6 to bind misfolded proteins. HDAC6 is an important regulator in aggresome formation, which represents an important cell survival strategy and is believed to contribute to proteasome inhibitor resistance.
In addition, literature research and in-house experiments indicated that pharmacological inhibition of HDAC6 failed to attain the same effects of genetic knockdown or knockout experiments and that therapeutic effects are often attributed to HDAC6-specific activity when actually non-selective inhibitory conditions were applied.
This information triggered us to explore inhibition of the ZUB of HDAC6 as a novel strategy and thus to develop compounds exhibiting a new mode of action.
These compounds will be evaluated in cell models of multiple myeloma (MM), a hematological cancer in which all of the patients eventually relapse and suffer from severe side effects. Considering the high dependency of MM on protein turnover for survival, this represents a valuable model.