Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

While histone deacetylases (HDACs) are known as modulators of epigenetic gene regulation, they also control the activity of non-histone protein substrates. The isozyme HDAC8 plays a role in inhibiting apoptosis and increasing cancer cell proliferation. As a result, HDAC8 is considered a potential target in the treatment of cancer forms such as T-cell lymphoma, gastric adenocarcinoma, hepatocellular carcinoma, and childhood neuroblastoma. The present work describes the development of proteolysis targeting chimera (PROTAC) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we have developed the first in class HDAC8 selective PROTAC and investigated the effect on protein degradation and on the proliferation of neuroblastoma cells. The combination of structure-guided synthesis, in vitro screening and cellular testing resulted in cereblon (CRBN) based HDAC8 PROTACs that showed anti-neuroblastoma activity in cells.