Histone deacetylases (HDACs) are a key class of proteins that are involved in chromatin remodeling and gene expression, and have been shown to regulate synaptogenesis and synaptic plasticity. There are 18 different HDAC enzymes in humans; several affect the expression of genes responsible for the creation and maintenance of synapses.
Inhibiting these HDACs activates a crucial switch that controls genes central to learning and memory. That makes HDAC inhibitors an attractive target for drug developers. But HDAC inhibitors are known to have dose limiting side effects and historically have not been used for long-term treatment of neurologic disorders.
At Rodin, we are designing compounds that selectively inhibit only specific HDAC complexes to drive increased neuronal gene expression while minimizing known class-based safety concerns.
Our initial focus is the HDAC-CoREST complex, which has been shown to be involved in repressing neuronal gene expression. Specific inhibition of the HDAC-CoREST complex reactivates neuronal gene expression, strengthens existing synapses and promotes the creation of new synapses, while minimizing dose-related side effects. This approach is further detailed in our recent publication.