Histone Deacetylase Inhibitors for Cancer Treatment

DESCRIPTION (provided by applicant): Histone deacetylases (HDACs) comprise a family of enzymes that catalyze the removal of acetyl groups from lysine residues of histones. They mediate chromatin remodeling and gene expression. HDAC inhibitors are potent inducers of growth arrest, differentiation or apoptic cell death and suppress cell proliferation in a variety of transformed cells in culture and in tumor bearing animals. Several HDAC inhibitors are in clinical trials as anticancer agents. Class I/I I histone deacetylases are metalloenzymes with a zinc ion at the active site. A crystal structure of a hydroxamate inhibitor bound to histone deacetylase showed that hydroxamates coordinate to the zinc ion. Hydroxamic acid appears to be the zinc ligand that almost all investigators use, even in 2004. However, hydroxamic acid derivatives often present metabolic and pharmacokinetic problems such as glucoronidation, sulfation and enzymatic hydrolysis that result in short in-vivo half lives. Nonhydroxamate HDAC inhibitors discovered so far have reduced potency compared to hydroxamates. There are currently 11 reported human class l/ll HDAC isoforms. A concerted effort has not been made for the development of HDAC isoform-selective inhibitors. Specific inhibition of HDAC isoforms for cancer may offer opportunities for improved specificity and reduced toxicity. Natural cyclic tetrapeptides are well known histone deacetylase inhibitors. Based on an inspection of SARs of known histone deacetylase inhibitors, an ideal HDAC inhibitor should be composed of an improved zinc binding ligand coupled through a spacer to the cyclic tetrapeptide core structure. Specific Aims: (1) The solid-phase synthesis of hydrophobic cyclic tetrapeptides as inhibitors of Zn(ll)-dependent histone deacetylases will be carried out. (2) Novel zinc ligands for the inhibition of histone deacetylase will be incorporated into the backbone of potent cyclic tetrapeptide analogues for further enhancement of activity. (3) These compounds will be assayed for histone deacetylase activity and for antitumor activity in a variety of cancer cells.