Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity

Histone deacetylases (HDACs) are
important modulators of epigenetic
gene regulation and additionally control the activity of non-histone
protein substrates. While for HDACs 1–3 and 6 many potent selective
inhibitors have been obtained, for other subtypes much less is known
on selective inhibitors and the consequences of their inhibition.
The present report describes the development of substituted benzhydroxamic
acids as potent and selective HDAC8 inhibitors. Docking studies using
available crystal structures have been used for structure-based optimization
of this series of compounds. Within this study, we have investigated
the role of HDAC8 in the proliferation of cancer cells and optimized
hits for potency and selectivity, both in vitro and in cell culture.
The combination of structure-based design, synthesis, and in vitro
screening to cellular testing resulted in potent and selective HDAC8
inhibitors that showed anti-neuroblastoma activity in cellular testing.