Histone deacetylase class I and IIb (HDAC Class I/IIb)

Histone deacetylases (HDACs) are a class of enzymes that play a critical role in epigenetic regulation by removing acetyl groups from lysine residues on histones and various non-histone proteins. The Zn2+-dependent Class I (HDAC1, 2, 3, and 8) and Class IIb (HDAC6 and 10) isoforms are key therapeutic targets due to their involvement in gene silencing and cellular homeostasis. Class I HDACs are primarily nuclear and regulate the cell cycle and apoptosis, while Class IIb HDACs, particularly HDAC6, are predominantly cytoplasmic and modulate cytoskeletal dynamics and protein degradation pathways. Dysregulation of these enzymes is linked to the progression of various cancers, neurodegenerative disorders, and inflammatory diseases. Pharmacological inhibition of these isoforms leads to hyperacetylation, which can restore the expression of tumor suppressor genes or disrupt the function of oncogenic proteins. Several HDAC inhibitors, such as vorinostat and romidepsin, have been approved for treating hematological malignancies, though achieving isoform selectivity remains a major challenge to minimize systemic toxicities. Beyond oncology, these targets are being explored for their potential in treating neurodegeneration by enhancing neuronal survival and reducing oxidative stress. The development of isoform-selective inhibitors is a primary focus in current drug discovery to improve the therapeutic window and reduce off-target effects.

Other names

HDAC1HDAC2HDAC3HDAC8HDAC6HDAC10Zinc-dependent histone deacetylases (Class I and IIb)Classical histone deacetylasesLysine deacetylases (KDACs)

Inhibition of the zinc-dependent catalytic site of HDAC enzymes, preventing the removal of acetyl groups from lysine residues on histones and non-histone proteins. This leads to hyperacetylation, chromatin relaxation, and altered gene expression (e.g., upregulation of p21), inducing cell cycle arrest, apoptosis, and differentiation.