Advances in the design and development of PROTAC-mediated HDAC degradation.

Abstract

Due to developments in modern chemistry, previously undruggable targets are becoming druggable thanks to selective degradation using the ubiquitin-proteasomal degradation system. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically to degrade target proteins (protein of interest, POI). They are of significant interest to industry and academia as they are highly specific and can target previously undruggable target proteins from transcription factors to enzymes. More than 15 degraders are expected to be evaluated in clinical trials by the end of 2021. Herein, we describe recent advances in the design and development of PROTAC-mediated degradation of histone deacetylases (HDACs). PROTAC-mediated degradation of HDACs can offer some significant advantages over direct inhibition, such as the use of substoichiometric doses and the potential to disrupt enzyme-independent HDAC function. Herein, we discuss the potential implications of the degradation of HDACs with HDAC knockout studies and the selection of HDAC inhibitors and E3 ligase ligands for the design of the PROTACs. The potential utility of HDAC PROTACs in various disease pathologies from cancer to inflammation to neurodegeneration is driving the interest in this field