Toward isozyme-selective inhibitors of histone deacetylase as therapeutic agents for the treatment of cancer

摘要

Since post-translational modifications of proteins are key mechanisms for controlling cellular function, targeting the machinery involved in these modifications offers new opportunities for the development of therapeutic agents. The histone deacetylases (HDACs) represent an important family of enzymes that are involved in controlling the acetylation state of key lysine residues in histones and other proteins. The development of HDAC inhibitors for the treatment of several diseases, most notably cancer, has proceeded rapidly. Recent attention has turned towards the development of isozyme-specific inhibitors that will provide selective targeting. It is believed that the ability to target-specific HDACs rather than all family members will lead to superior therapeutics with better efficacy and lower toxicity. A review of recent patents shows that researchers are targeting a wide range of isozymes and that key advances in the structural biology of HDACs are providing important design information.