PRMT5, PRMT6 and PRMT8 [68]. In vivo studies show a decrease of H4R3me2a,
but not H3R2me2a, H3R17me2a or sDMA in cocaine treated mice.
3.3 Biological Relevance of Inhibitors and Current Outlook
As the predominant member of the arginine methyltransferase family, PRMT1 has
been the subject of thorough investigation and aims at identifying potent and
selective inhibitors. Thus far, limited success has been achieved. To date, the most
potent inhibitors reported show activity in the micromolar range, and the compounds
are often active against at least one more PRMT. At present, no potent and selective
inhibitors have been described for PRMT1. Studies investigating the role of PRMT1
in healthy and disease states show its upregulation in malignant cell lines. Cellular
assays performed with a number of the inhibitors described above show their
efficacy in killing tumour cell lines. Such promising results underscore the importance of developing potent and selective PRMT1 inhibitors.
4 PRMT2
4.1 Background
The second member identified as part of the PRMT family [10], PRMT2, is among
the least studied PRMTs. PRMT2 is a type I PRMT, producing both MMA and
aDMA. While it exhibits weak activity for histone H4 methylation [97], only few
unique substrates for PRMT2 have been identified to date [98]. PRMT2 resides
mainly in the nucleus, interacts with splicing factors and is a coactivator of nuclear
hormone receptors, including the androgen and oestrogen α receptors [99–
101]. PRMT2 regulates leptin signalling by methylation of STAT3 (signal transducer and activator of transcription 3) [102] and is downregulated under high
glucose conditions leading to increased atherosclerosis through reduced cholesterol
efflux [103]. PRMT2 is also associated with survival outcome and tumour grade in
breast cancer via transcriptional activation of oestrogen receptor α [43, 104, 105].
4.2 Inhibitors: In Vitro and Cell-Based Activities
In addition to its weak methylating activity towards histones and the limited knowledge on nonhistone substrates, very few PRMT2 inhibitors have been reported. In a
recent paper describing the crystal structure of PRMT2 [98], repressor splicing factor
1 (RSF1) was identified as a new nonhistone substrate. PRMT2 was found to
methylate RSF1 much more efficiently than histone H3 or H4. Crystal structures
170
M. J. van Haren and N. I. Martin
but not H3R2me2a, H3R17me2a or sDMA in cocaine treated mice.
3.3 Biological Relevance of Inhibitors and Current Outlook
As the predominant member of the arginine methyltransferase family, PRMT1 has
been the subject of thorough investigation and aims at identifying potent and
selective inhibitors. Thus far, limited success has been achieved. To date, the most
potent inhibitors reported show activity in the micromolar range, and the compounds
are often active against at least one more PRMT. At present, no potent and selective
inhibitors have been described for PRMT1. Studies investigating the role of PRMT1
in healthy and disease states show its upregulation in malignant cell lines. Cellular
assays performed with a number of the inhibitors described above show their
efficacy in killing tumour cell lines. Such promising results underscore the importance of developing potent and selective PRMT1 inhibitors.
4 PRMT2
4.1 Background
The second member identified as part of the PRMT family [10], PRMT2, is among
the least studied PRMTs. PRMT2 is a type I PRMT, producing both MMA and
aDMA. While it exhibits weak activity for histone H4 methylation [97], only few
unique substrates for PRMT2 have been identified to date [98]. PRMT2 resides
mainly in the nucleus, interacts with splicing factors and is a coactivator of nuclear
hormone receptors, including the androgen and oestrogen α receptors [99–
101]. PRMT2 regulates leptin signalling by methylation of STAT3 (signal transducer and activator of transcription 3) [102] and is downregulated under high
glucose conditions leading to increased atherosclerosis through reduced cholesterol
efflux [103]. PRMT2 is also associated with survival outcome and tumour grade in
breast cancer via transcriptional activation of oestrogen receptor α [43, 104, 105].
4.2 Inhibitors: In Vitro and Cell-Based Activities
In addition to its weak methylating activity towards histones and the limited knowledge on nonhistone substrates, very few PRMT2 inhibitors have been reported. In a
recent paper describing the crystal structure of PRMT2 [98], repressor splicing factor
1 (RSF1) was identified as a new nonhistone substrate. PRMT2 was found to
methylate RSF1 much more efficiently than histone H3 or H4. Crystal structures
170
M. J. van Haren and N. I. Martin