Towards Isozyme-Selective HDAC Inhibitors For Interrogating Disease

Praveer      Gupta; Robert      C. Reid; Abishek      Iyer; Matthew      J. Sweet; David      P. Fairlie

Abstract

Histone deacetylase (HDAC) enzymes have emerged as promising targets for the treatment of a wide range of human diseases, including cancers, inflammatory and metabolic disorders, immunological, cardiovascular, and infectious diseases. At present, such applications are limited by the lack of selective inhibitors available for each of the eighteen HDAC enzymes, with most currently available HDAC inhibitors having broad-spectrum activity against multiple HDAC enzymes. Such broad-spectrum activity maybe useful in treating some diseases like cancers, but can be detrimental due to cytotoxic side effects that accompany prolonged treatment of chronic diseased states. Here we summarize progress towards the design and discovery of HDAC inhibitors that are selective for some of the eleven zinc-containing classical HDAC enzymes, and identify opportunities to use such isozyme-selective inhibitors as chemical probes for interrogating the biological roles of individual HDAC enzymes in diseases.

Keywords: Histone deacetylase, HDAC inhibitor, isoform, isozyme, cancer, inflammation, metabolic, promising targets, immunological, cardiovascular, cytotoxic, lysine residues, cellular proteins, phosphorylation, small molecule chemical inhibitors, therapeutic drugs