Class IIa and Class IV histone deacetylases (Class IIa/IV HDACs)

Class IIa and Class IV Histone Deacetylases (HDACs) are a subset of zinc-dependent enzymes that regulate gene expression and protein function by removing acetyl groups from lysine residues on histones and non-histone proteins [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433956/]. Class IIa includes HDAC4, HDAC5, HDAC7, and HDAC9, which are characterized by their ability to shuttle between the nucleus and cytoplasm and their tissue-specific expression in the brain, heart, and muscle [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468131/]. HDAC11 is the sole member of Class IV and is the smallest histone deacetylase, playing key roles in immune regulation and metabolic homeostasis [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619143/]. These enzymes are critical therapeutic targets in oncology, where they often silence tumor suppressor genes, and in inflammatory and neurodegenerative diseases [PubMed, https://pubmed.ncbi.nlm.nih.gov/28605915/]. Therapeutic targeting of these HDACs has primarily involved pan-HDAC inhibitors like vorinostat and romidepsin, which are approved for hematological malignancies but are limited by systemic toxicities such as myelosuppression and cardiotoxicity [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085879/]. Consequently, there is significant ongoing research into class-selective and isoform-selective inhibitors, such as TMP269 and tasquinimod, which aim to provide more targeted therapy with improved safety profiles [Drug Target Review, https://www.drugtargetreview.com/news/148433/class-iia-hdac-inhibition-a-potential-therapy-for-inflammatory-diseases/].

Other names

HDAC4HDAC5HDAC7HDAC9HDAC11Lysine deacetylasesKDACsHistone deacetylase 4Histone deacetylase 5Histone deacetylase 7Histone deacetylase 9Histone deacetylase 11

Class IIa and Class IV HDAC inhibitors primarily act by chelating the zinc ion (Zn2+) within the enzyme's catalytic pocket, thereby blocking the deacetylation of lysine residues on histone tails and non-histone proteins [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468131/]. This inhibition leads to the hyperacetylation of these substrates, which promotes an open chromatin structure (euchromatin) and facilitates the transcriptional reactivation of silenced genes, such as those involved in cell cycle arrest and apoptosis [NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433956/]. Additionally, these HDACs modulate the activity of various transcription factors, including MEF2 and HIF1-alpha, influencing pathways related to muscle differentiation, angiogenesis, and immune cell function [PubMed, https://pubmed.ncbi.nlm.nih.gov/28605915/].