Arginine Methyltransferase Inhibitors

As an alternative approach an adenosine-derived mustard was developed as a PRMT inhibitor by a strategy that was based on the mechanism of the enzyme. This compound is an alkylating agent which is covalently attached to a peptide substrate only upon incubation with PRMTl [80]. It is not very druglike and is more of a chemical tool. 

For lysine methyltransferases few specific inhibitors have been reported so far and all were discovered by random screening procedures. The first inhibitor that was 

The compound BIX-01294 was identified as an inhibitor of G9a in the low micromolar region and a selectivity against SUV39H1 and PRMTl was shown. BIX-01294 also showed a reduction of the methylation levels of H3K9 dimethylation. Known sites of other lysine methyltransferases like H3K27 or H4K20 were not affected. In the same study dual inhibitors of arginine and lysine methyltransferases like BIX-01338 were reported [82], 

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

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

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

During the past several years, a variety of crystal structures of histone lysine and arginine methyltransferase in complex with the cofactor analog SAH and/or in complex with peptide substrates have been reported [92]. However, no 3D structure of a complex between a histone methyltransferase (HMT) and an inhibitor has been reported so far. Due to the lack of experimental structures, a variety of molecular modeling and docking studies has been carried out for H MTs in order to understand the structural requirements for inhibitor binding. 

Purandare, A.V., Chen, Z., Huynh, T, Pang, S., Geng, J., Vaccaro, W Poss, M.A., Oconnell, J., Nowak, K. and Jayaraman, L. (2008) Pyrazole inhibitors of coactivator associated arginine methyltransferase 1 (CARMl). Bioorganic ej Medicinal Chemistry Letters, 18, 4438-4441. 

Virtual Screening and Biological Characterisation of Novel Histone Arginine Methyltransferase PRMTl Inhibitors. 3 (in press). 

Jung et al. applied this approach to develop inhibitors for a histone modifying enzyme - the histone arginine methyltransferase PRMTl.An identical PRMTl inhibitor with cellular activity was obtained which blocks both the cofactor S-adenosylmethionine (SAM) and the substrate... 

Structure-Based VS for Histone Arginine Methyltransferase PRMT1 Inhibitors... 

Kleinschmidt MA, de Graaf P, van Teeffelen HA, Timmers HT. Cell cycle regulation by the PRMT 6 arginine methyltransferase through repression of cyclin-dependent kinase inhibitors. PLoS One. 2012 55 7978-87. 

Thiadiazoles are incorporated into the allosteric inhibitor ofPRMT3 (protein arginine methyltransferase 3) 163 (13JMC2110), and inhibitor of TAKl (transforming growth factor p receptor-associated kinase 1) 164 (13BMCL4517). 

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