Small Molecule Inhibitors of Zinc-dependent Histone Deacetylases

Lysine acetylation is an ancient, evolutionarily conserved, reversible post-translational modification. A multitude of diverse cellular functions are regulated by this dynamic modification, including energy and metabolism, protein folding, transcription, and translation. Gene expression can be manipulated through changes in histone acetylation status, and this process is controlled by the function of 2 opposing enzymes: histone acetyl transferases and histone deacetylases (HDACs). The zinc-dependent HDACs are a family of hydrolases that remove acetyl groups from lysines, and their function can be modulated by the action of small molecule ligands. Inhibition through competitive binding of the catalytic domain of these enzymes has been achieved by a diverse array of small molecule chemotypes. Structural biology has aided the development of potent, and in some cases highly isoform-selective, inhibitors that have demonstrated utility in a number of neurological disease models. Continued development and characterization of highly optimized small molecule inhibitors of HDAC enzymes will help refine our understanding of their function and, optimistically, lead to novel therapeutic treatment alternatives for a host of neurological disorders.