Targeted Protein Degradation of Histone Deacetylases by Hydrophobically Tagged Inhibitors

There is a growing interest in alternative strategies for targeted protein degradation. In this work, we present the development of histone deacetylase (HDAC) degraders based on hydrophobic tagging technology. To this end, a library of hydrophobically tagged HDAC inhibitors was synthesized via efficient solid-phase protocols utilizing pre-loaded resins. The subsequent biological evaluation led to the identification of our best degrader, 1a, which significantly decreased HDAC1 levels in MM.1S multiple myeloma cells.