The vast majority of DNA in eukaryotic cells is tightly wrapped around core histone proteins, forming the so-called chromatin. The accessibility of the DNA is dependent on the chromatin structure which can be altered by posttranslational modifications (PTMs) of the N-terminal tails of histone proteins. Consequently, gene expression can be altered by certain histone modifications; e.g. phosphorylation of histones leads to gene activation by making the DNA accessible for RNA poylmerases. So far, more than 70 different sites for histone PTMs have been identified; the different types of histone PTMs include phosphorylation, acetylation, methylation, SUMOylation, biotinylation, hydroxylation and ubiquitylation. The large number of modification sites and the diversity among them show the importance of histone PTMs towards gene regulation. As the strict regulation of gene expression patterns is crucial for the normal cell function, mal-function of histone-modifying enzymes could play a central role in disease development, making histone modifying enzymes possible drug targets.
Histone demethylation is one of the most interesting and ambigious histone modifications. As methylation does not alter the charge of the histone protein, it can result in both gene activation and repression. Lysine residues of histone proteins can be either methylated once, twice or three times; these different methylation states yield a considerable diversity in the possible biological outcome of this modification. The histone demethylases from the Jmj2C family have been linked to promotion of tumor growth, X-linked mental retardation and cleft lip palate. Therefore, these enzymes are considered oncogenes; their selective inhibition might be a possible therapeutic approach to treat cancer. However, the development of selective inhibitors appears to be difficult due to the high sequence and structure similarity within this protein family. The histone demethylase small-molecule inhibitors developed so far inhibit also other histone-modifying enzymes. A possible approach to overcome this problem would be the development of highly specific, targeted drugs. Such targeted drugs could consist of so called peptidomimetics coupled to small molecule inhibitors. The selectivity of these drugs would be promoted through the peptidomimetic part of the drug that imitates the enzyme substrate.
The overall goal of this project is to synthesize and biochemically characterize highly selective and potent inhibitors for histone demethylases from the Jmj2C family.