Histone deacetylase inhibitors

Overview

Histone deacetylase inhibitors (HDAC inhibitors) are a class of anticancer and experimental therapeutic agents that block the activity of histone deacetylases—enzymes that remove acetyl groups from lysine residues on histone and non-histone proteins. Inhibition of HDAC activity leads to hyperacetylation of histones, resulting in a more open chromatin structure and altered transcription of genes involved in cell cycle regulation, differentiation, and apoptosis. Beyond oncology, HDAC inhibitors are also being studied for neurological, inflammatory, and fibrotic diseases.

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Mechanism of Action

• Histone modification: HDAC inhibition prevents deacetylation of histones, maintaining chromatin in a relaxed state, which promotes transcription of tumor suppressor genes.

• Non-histone targets: HDACs also regulate transcription factors, chaperone proteins, and structural proteins (e.g., p53, HSP90, α-tubulin); their acetylation status influences stability, localization, and activity.

• Biological effects: Induce cell cycle arrest (often G1 or G2/M), promote apoptosis, inhibit angiogenesis, and can modulate immune response by increasing expression of tumor antigens and immune-related genes.

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Classification by HDAC Target Specificity

• Pan-HDAC inhibitors – target multiple HDAC classes (vorinostat, panobinostat).

• Class I selective inhibitors – preferentially inhibit nuclear HDACs (romidepsin, entinostat).

• Class II selective inhibitors – more cytoplasmic activity (ricolinostat—HDAC6 selective).

• Class IV inhibitors – still under investigation, more niche biological roles.

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Approved Therapeutic Uses

• Oncology (mainly hematologic malignancies)

  • Vorinostat – Cutaneous T-cell lymphoma (CTCL)

  • Romidepsin – CTCL and peripheral T-cell lymphoma (PTCL)

  • Belinostat – Relapsed or refractory PTCL

  • Panobinostat – In combination with bortezomib and dexamethasone for multiple myeloma

• Investigational uses in solid tumors, neurodegenerative disorders (Huntington’s disease, Alzheimer’s disease), autoimmune conditions, and fibrosis.

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Commonly Used HDAC Inhibitors and Brand Names

• Vorinostat (Zolinza)

• Romidepsin (Istodax)

• Belinostat (Beleodaq)

• Panobinostat (Farydak)

• Chidamide (China-approved; oral, selective HDAC1, 2, 3, 10)

• Valproic acid – primarily an anticonvulsant/mood stabilizer, but also a weak HDAC inhibitor

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Adverse Effects

• Hematologic: Thrombocytopenia, neutropenia, anemia

• Gastrointestinal: Nausea, vomiting, diarrhea, anorexia

• Constitutional: Fatigue, asthenia, fever

• Cardiac: QT prolongation (especially with romidepsin and panobinostat), arrhythmias

• Metabolic: Electrolyte abnormalities (hypokalemia, hypomagnesemia)

• Others: Infections due to immunosuppression

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Contraindications and Precautions

• Baseline QT prolongation or significant cardiac disease

• Uncontrolled infections

• Severe hepatic impairment (dose adjustments or avoidance may be required)

• Pregnancy – teratogenic risk observed in animal studies

• Caution with pre-existing cytopenias

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Drug Interactions

• QT-prolonging drugs (e.g., certain antiarrhythmics, fluoroquinolones, macrolides) – additive risk

• Strong CYP3A4 inhibitors/inducers – may alter plasma levels of certain HDAC inhibitors (especially panobinostat and belinostat)

• Valproic acid – may have additive HDAC inhibition and overlapping toxicities when combined with other HDAC inhibitors

• Drugs causing electrolyte imbalances – may exacerbate arrhythmia risk