Methyltransferase Inhibitors

Chrebet, G. L., Wisniewski, D., Perkins, A. L., Deng, Q., Kurtz, M. B., Marcy, A., and Parent, S. A. (2005). Cell-based assays to detect inhibitors of fungal mRNA capping enzymes and characterization of Sinefungin as a cap methyltransferase inhibitor.J. Biomol. Screen. 10, 355-364. 

Stresemann, C., Brueckner, B., Musch, T., Stopper, H. and Lyko, F. (2006) Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Research, 66, 2794—2800. 

Mai, A., Valente, S., Cheng, D., Perrone, A., Ragno, R., Simeoni, S. et al. (2007) Synthesis and biological validation of novel synthetic histone/protein methyltransferase inhibitors. ChemMedChem, 3, 987-991. 

Heinke, R., Spannhoff A., Huda, E., Meier, R., Jung, M. and Sippl, W. (2009) Virtual screening and biological characterization of histone methyltransferase inhibitors PRMTl. ChemMedChem, 4, 69-77. 

Spannhoff A., Machmur, R., Heinke, R., Trojer, P., Bauer, I., Brosch, G. etal. (2007) A novel arginine methyltransferase inhibitor with cellular activity. 

Hydralazine is a vasodilating drug and inhibition of DNA methyltransferases in the range of 10-20 pM have been reported in vitro [83]. In addition, hypomethylation in cell culture has also been shovm [84]. Also the local anesthetic procaine [85] and its amide analog procainamide [84] have been identified as DNA methyltransferase inhibitors. Synthetic analogs of procaine have shown activity only around 500 pM [86] (Figure 8.10). 

Brueckner, B., Kuck, D. and Lyko, F. (2007) DNA methyltransferase inhibitors for cancer therapy. Cancer Journal (Sudbury, Mass), 13, 17-22. 

Stresemarm, C. and Lyko, F. (2008) Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. International Journal of Cancer, 123, 8-13. 

Zhu, W.G. and Otterson, G.A. (2003) The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. Current Medicinal Chemistry Anticancer Agents, 3, 187-199. 

Various epigenetic targets have been investigated in drug discovery approaches. So far only HDAC and DNA methyltransferase (DNMT) inhibitors are approved for the treatment of human cancer or are currently investigated in clinical studies [69]. The search for histone methyltransferase inhibitors is far less developed. 

Figure 12.2 Arginine methyltransferase inhibitors from random and virtual screening campaigns (IC50 values in brackets if no enzyme is mentioned, against hPRMTI).

Figure 12.4 Lysine methyltransferase inhibitors (all from random screening, IC50 values and enzymes in brackets).

Although the field of histone methyltransferase inhibitors is still in its infancy in terms of drug discovery, a lot of kno vledge in terms of their biological roles has been acquired. Test systems for in vitro and in vivo evaluation are available and model approaches have been presented already that led to inhibitors of these enzymes with promising cellular activity. Therefore, a dynamic development of the field can be expected vhich hopefully vill lead to clinical candidates in the upcoming years. 

A novel arginine methyltransferase inhibitor with cellular activity. Bioorganic ej Medicinal Chemistry Letters, 17, 4150-4153. 

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