Histone deacetylase inhibitors

Histone deacetylases (HDACs) are a class of enzymes found in bacteria, fungi, plants and animals that remove the acetyl group from the ε-amino groups of lysine residues located in the NH2 terminal tails of core histones.

There are 18 known human histone deacetylases, grouped into four classes based on the structure of their accessory domains.

Class I includes HDAC1, HDAC2, HDAC3, and HDAC8 and have homology to yeast RPD3. HDAC4, HDAC5, HDAC7, and HDAC9 belong to class II and have homology to yeast HDA1. HDAC6 and HDAC10 contain two catalytic sites and are classified as class IIa, whereas HDAC11 has conserved residues in its catalytic center that are shared by both class I and class II deacetylases and is sometimes placed in class IV.

Histone deacetylase inhibitors (HDACIs) are emerging as a new class of potential anticancer agents and have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addition, these compounds inhibit tumor growth in animal models and show antitumor activity in patients.

The interest in HDAC inhibitors began almost 30 years ago during some studies designed to understand why dimethyl sulfoxide (DMSO) caused terminal differentiation of murine erythroleukemia cells.

In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified that inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in culture and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumor and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitors in vivo.

In October 2006 the FDA approved the first HDAC inhibitor – Vorinostat (Zolinza, Suberoylanilide hydroxamic acid, formerly known as SAHA, Merck & co) to treat the rare cancer cutaneous T-cell lymphoma (CTCL). At least 12 different HDACIs are currently in some phase of clinical trials as monotherapy or in combination chemotherapy or radiation therapy in patients with hematologic and solid tumors, including lung, breast, pancreas, renal, and bladder cancers, melanoma, glioblastoma, leukemias, lymphomas, and multiple myeloma.

The focus of this website is information about molecules or drugs that block HDACs (HDAC inhibitors).

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