Project: Innovative Treatment of Cancer by Selective Protection of Histones from Methylation

Cancer represents a group of more than 200 different, often life-threatening diseases. Despite improved treatment options, the need for additional and novel therapeutic strategy is still very high and even increasing. This is e.g. due to the increasing number of patients, the still limited curative success rate, and the significant adverse side effects of many approved cancer drugs. _x000D_Histones are proteins that interact with the chromosomal DNA thus regulating the expression of a large number of genes. The healthy expression of these genes is achieved by controlled modification of the histones; a process that is called epigenetic regulation. Histones e.g. can be phosphorylated, actelylated, and methylated resulting in a change of the ability of the histones to interact with the DNA. In general, release of DNA from histones leads to an increase of gene expression, whereas enhance interaction favours gene repression._x000D_In many cancers alteration of histone modificating enzymes are found causing pathological changes in the expression of genes and the development of cancer. First drugs e.g. inhibiting histone deacetylases (HDAC) have been approved for the treatment of some hematological cancers supporting the therapeutic value of epigenetic intervention (1). However, HDACs are rather unspecific enzymes, and acetylate also many non-histone proteins, and, hence, their exact molecular mode of action is uncertain. Furthermore, clinical efficacy in solid tumours that represent more then 90% of all cancer are limited (2)._x000D_Apart from HDACs, additional histone modifying enzyme classes have been identified that are responsible for modulation of gene expression. _x000D_The family of lysine methyltransferases (KMT) comprises more than 40 distinct enzymes that, with one exception, carry a so called SET doCO harbouring the region of enzymatic activity. _x000D_In the last couple of years several KMTs such as NSD3, EHMT2,and SMYD3 have been found upregulated in various types of human tumours (3) while other KMT such as SMYD4 and EHMT1 are loss in some tumour types (4,5). Increasing evidence demonstrate that upregulated KMTs can act as oncogenic drivers which qualify them as potential targets for therapeutic intervention. Inhibition of e.g. NSD3 in breast cancer cells suppresses proliferation(6). EHMT2 promotes migration and invasiveness of human lung cancer cell lines which can be suppressed by a dominant negative EHMT2 mutant(7). RNA-interference mediated knock down of SMYD3 in colon cancer cells results in significant growth inhibition(8). _x000D__x000D_Taken together, these data indicate that compounds that selectively inhibit oncogenic KMTs bear huge potential as novel cancer drugs._x000D__x000D_This Eureka proposal describes the combined action of ProQinase (Germany) and Mercachem (The Netherlands) to develop novel KMT-inhibitors as a base for medicines against many cancers. Although this project is highly complex regarding the selectiveness of KMT-inhibitors, ProQinase and Mercachem strongly believe that they can carry out this project successfully for the following reasons:_x000D__x000D_• ProQinase, a German R&D performing SME has extensive knowledge of KMT biology, oncology, and drug development; has established high throughput screening technologies for chemical compounds; has established comprehensive collections of cellular and in vivo tumour models for the discovery and development of cancer drugs._x000D__x000D_• Mercachem, a Dutch R&D performing SME has a strong background in the development of novel, complex chemical compounds, fragment based drug design, medicinal chemistry, parallel chemistry, building chemical libraries; and lead optimization trajectories. _x000D__x000D_• The large family of KMT’s allows the development of many KMT-inhibiting compounds with highly different chemical and biological properties. In fact, both ProQinase and Mercachem have already a clear strategy where to start this development. _x000D__x000D_• ProQinase and Mercachem already work for pharmaceutical and biotech industries worldwide and contribute significantly to the development of many new medicines. _x000D__x000D_• There is little doubt that the pharmaceutical and biotech industries are willing to pay considerably for preclinical lead candidates for KMT-inhibition and for further joint developments together with ProQinase and Mercachem. The worldwide market size for anti-cancer medicines is ~ EUR 60 bn and is growing rapidly whereas only very few cancer-diseases can be cured effectively; while many medicines have strong side-effects.

Acronym iSelect (Reference Number: 7300)
Duration 01/10/2012 - 30/09/2015
Project Topic The goal of the iSELECT-project is to develop novel inhibitors of Lysin-Methyltransferases (KMT) deregulated in cancer. This will be achieved by an innovative approach combining screening of target family-centric compound libraries against a set of KMTs and multifactorial cellular phenotypic testing
Network Eurostars
Call Eurostars Cut-Off 8

Project partner

Number Name Role Country
2 KTB Tumorforschungsgesellschaft mbH Coordinator Germany
2 Mercachem Holding B.V. Partner Netherlands