Methyltransferases are involved in epigenetic gene regulation by covalent modification of histones. An ever-increasing body of evidence indicates that these enzymes are significant in many diseases, and that they play important roles in stem-cell biology. In particular, a number of these enzymes are known to be of relevance in some mechanisms of carcinogenesis.
Domainex has solved the key technical drug discovery challenges associated with KMTs, including generating a number of proprietary crystal structures, assays and a novel screening library of small molecule inhibitors. Targets of interest currently include, but are not limited to, G9a and EZH2.
Domainex's KMT discovery programme
Domainex is at the forefront of epigenetic drug discovery and a world player in this field. It has utilized its core platform technologies to enable it to develop an impressive early discovery pipeline focussed on the lysine methyltransferase (KMTS) class of targets.
There are key challenges in the study of KMTs, and Domainex has succeeded in establishing a platform on which to build a robust pipeline. It has:
- Cloned and expressed a number of lysine methyltransferase enzymes (KMTs), making use of its proprietary Combinatorial Domain Hunting (CDH) technology.
- Determined the crystal structure of a number of the KMTs and these protein structures are proving extremely useful for the design of inhibitors.
- Established a range of biochemical systems that can be utilized across the target class, for example, using peptide, full-length histone H3, or higher complexes of H3.
Finally, Domainex has developed an entirely novel screening library of small molecules which can be utilized across the KMT enzyme class. At present four of these programmes are in the early lead optimization stage of drug discovery and continue to progress well.