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Isoform-selective histone deacetylase inhibitors: the trend and promise of disease treatment.

Epigenetics is generally referred to the heritable phenotype changes resulting from regulation of gene expression through chromosome modification but not DNA sequence alteration. In addition to DNA methylation, abundant epigenetic modifications to chromatin histones, such as methylation, ubiquitination, phosphorylation and acetylation, are catalyzed by pairs of enzymes with converse activity. Among these epigenetic enzymes, histone deacetylases (HDACs) have drawn most attention from both academia and industry. To date, 18 human HDAC isoforms have been identified which are divided into four classes based on their phylogenetic homology, cellular localization and substrate specificity. In the past 10 years, over 490 clinical trials of more than 20 HDAC inhibitors (HDACIs) mainly as antitumor agents have been initiated. However, most HDACIs in clinic are so-called pan-HDACIs (such as vorinostat, panobinostat, belinostat and abexinostat), which inhibit broad-spectrum HDACs. Such pan-HDACIs may be useful and acceptable in treating cancers, but can be detrimental and unacceptable due to cytotoxic side effects resulting from prolonged treatment of some chronic diseases. Actually, significant toxicities including fatigue, nausea, vomiting, thrombocytopenia and neutropenia of HDACIs have been reported in cancer treatment [1]. Therefore, development of HDACIs selective for a single class or isoform with the expectation of better tolerance and fewer side effects has become a hot topic. Nowadays, some class selective and even isoform-selective inhibitors have been reported. Interested readers can refer to review [2] and [3]. Over years of research and practice, class I-selective HDACIs have developed into a type of relatively successful compounds with HDAC1/2 selective cyclic depsipeptide FK228, HDAC1/2/3 selective benzamides MS-275 and MGCD0103 in clinical trials. However, these class I-selective HDACIs and pan-HDACIs seem to share similar toxicity profiles and overall tolerability at clinically relevant doses. Inspiringly, many researches have demonstrated that simultaneous deletion or inactivation of both HDAC1 and HDAC2 produces obvious deleterious effects on the development of neuron [4], oligodendrocyte [5], Schwann cell [6,7], kidney [8], heart [9], epidermis [10], B cell [11], T cell [12], hematopoiesis [13] and oocyte [14], which may partially explain the reason why the toxicity of class I-selective HDACIs is not significantly different from that of nonselective compounds. However, in most aforementioned cases, conditional deletion or inactivation of HDAC1 or HDAC2 alone does not result in obvious defects due to the redundant or overlapping functions of the two class I HDAC isoforms [4–14]. Based on the above information, can we postulate that some toxic effects of class I-selective HDACIs come from simultaneous inhibition of HDAC1 and HDAC2? If so, can class I-selective HDACIs be endowed with ameliorated toxicity profiles while maintaining antitumor activity if they lose the inhibition against either HDAC1 or HDAC2? Isoform-selective histone deacetylase inhibitors: the trend and promise of disease treatment