Isoform-selective HDAC inhibitors: closing in on translational medicine for the heart

Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. However, since broad-spectrum, "pan" HDAC inhibition is associated with toxicities such as thrombocytopenia, nausea and fatigue, many in the field remain skeptical of the prospects of translating these findings to the heart failure clinic. Robust medicinal chemistry efforts in industry and academics have led to the discovery of small molecules that selectively inhibit one or a small subset of the 18 human HDACs, and many of these compounds appear to exhibit improved safety profiles. This work has set the stage for identification of the HDAC isoform(s) that promote pathological cardiac remodeling, and advancement of safer HDAC inhibitors into clinical trials for heart failure. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure".