Histone deacetylase inhibitors in cancer therapy: latest developments, trends and medicinal chemistry perspective.
Regulation of gene expression is mediated by several mechanisms such as DNA methylation, ATP-dependent chromatin remodeling, and post-translational modifications of histones. The latter mechanism includes dynamic acetylation and deacetylation of epsilon-amino groups of lysine residues present in the tail of the core histones. Enzymes responsible for the reversible acetylation/deacetylation processes are histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. There are three mammalian HDAC families, namely HDACs I, II and III based on their sequence homology. Inhibitors of HDACs induce hyperacetylation of histones that modulate chromatin structure and gene expression resulting in growth arrest, cell differentiation, and apoptosis of tumor cells. In addition, HDAC inhibitors enhance efficacy of anticancer agents that target DNA. Several formidable challenges associated with their development include non-specific toxicity and poor PK properties, including cell permeability. In this review, we comment on the current progress in design, discovery, in vitro/ex vivo activity and clinical potential of the synthetic modulators of HDACs.
Balakin
Konstantin V
KV
ChemDiv, Inc. 6605 Nancy Ridge Dr. San Diego, CA 92121, USA. kb@chemdiv.com
Ivanenkov
Yan A
YA
Kiselyov
Alex S
AS
Tkachenko
Sergey E
SE
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases