histondeacetylaseinhibitors

Histone deacetylase inhibitors are a class of epigenetic drugs that block histone deacetylases, enzymes that remove acetyl groups from lysine residues on histones and other proteins. Inhibition increases histone acetylation, leading to an open chromatin state and altered transcription. This can promote cell cycle arrest, differentiation, and apoptosis in tumor cells, and can also affect non-histone proteins involved in signaling, stability, and immune recognition.

HDACs are organized into four classes: Class I (HDAC1,2,3,8), Class IIa (HDAC4,5,7,9), Class IIb (HDAC6,10), Class III (sirtuins), and Class IV (HDAC11). Inhibitors can be pan-HDAC inhibitors or isoform-selective. Clinically approved drugs include vorinostat and romidepsin for cutaneous T-cell lymphoma, belinostat for peripheral T-cell lymphoma, and panobinostat for multiple myeloma. Other agents such as chidamide are approved in China and entinostat and others are studied in various cancers. Many HDAC inhibitors are zinc-dependent and bind to the catalytic site.

Antitumor activity arises from re-expression of silenced genes, such as p21, induction of cell cycle arrest, apoptosis, and differentiation. They can enhance the effect of DNA-damaging therapies and have immunomodulatory effects. Non-histone substrates include p53, tubulin, and HSP90, contributing to diverse biological outcomes. Side effects commonly include fatigue, nausea, thrombocytopenia, anemia, QT interval prolongation, and electrolyte imbalances; cardiac toxicity limits some regimens. Resistance can develop, and toxicity often requires careful patient selection and monitoring.

Research continues to expand the therapeutic potential of HDAC inhibitors beyond oncology, exploring neurodegenerative diseases, inflammatory disorders, and HIV latency reversal, among others. Strategies to improve selectivity and reduce toxicity include isoform-specific inhibitors, combination therapies, and targeted delivery.