9.3 Biological Relevance of Inhibitors and Current Outlook
Very limited work has been done in the development of PRMT7 inhibitors. Currently,
no potent and specific PRMT7 inhibitors are available. However, interesting recent
findings suggest PRMT7 is a viable therapeutic target, e.g. for (re-)sensitising tumour
cells to chemotherapeutic agents or for the treatment of breast cancer.
10 PRMT8
10.1 Background
The eighth member of the PRMT family is a type I PRMT that is primarily expressed
in the brain and is myristoylated at the N-terminal glycine, both unique features
within the PRMT family [17]. The myristoylation of PRMT8 results in its association with the plasma membrane. Cleavage of the N-terminal domain results in an
increase in methylation activity [192], and a variant (PRMT8v2) lacking the
N-terminal glycine was found to be located primarily in the nucleus rather than the
cell membrane [193, 194]. PRMT8 has high sequence similarity with PRMT1 (about
80%) and methylates the GAR motif.
Recent studies point to an involvement of PRMT8 in amyotrophic lateral sclerosis (ALS) [195] and high expression levels of PRMT8 are linked to a variety of
cancers [196]. Furthermore, knockdown of PRMT8 halted cell proliferation and
caused cell death in both healthy human dermal fibroblasts and U87MG glioblastoma cells [194].
10.2 Inhibitors: In Vitro and Cell-Based Activities
No specific inhibitors have been developed against PRMT8. Interestingly,
ethylenediamino-containing compounds (fragment 49 [134], MS049 (51) [135],
Fig. 11) that were active against PRMT4 and PRMT6 were also generally active
against PRMT8. In addition, the covalent inhibitors 28 and 29 [91] (Fig. 6) designed
to interact with the active site cysteine found in PRMT1 were also found to be active
against PRMT8. This is not surprising given the high sequence similarity, including
the presence of an active site cysteine, between these two PRMTs.
184
M. J. van Haren and N. I. Martin
Very limited work has been done in the development of PRMT7 inhibitors. Currently,
no potent and specific PRMT7 inhibitors are available. However, interesting recent
findings suggest PRMT7 is a viable therapeutic target, e.g. for (re-)sensitising tumour
cells to chemotherapeutic agents or for the treatment of breast cancer.
10 PRMT8
10.1 Background
The eighth member of the PRMT family is a type I PRMT that is primarily expressed
in the brain and is myristoylated at the N-terminal glycine, both unique features
within the PRMT family [17]. The myristoylation of PRMT8 results in its association with the plasma membrane. Cleavage of the N-terminal domain results in an
increase in methylation activity [192], and a variant (PRMT8v2) lacking the
N-terminal glycine was found to be located primarily in the nucleus rather than the
cell membrane [193, 194]. PRMT8 has high sequence similarity with PRMT1 (about
80%) and methylates the GAR motif.
Recent studies point to an involvement of PRMT8 in amyotrophic lateral sclerosis (ALS) [195] and high expression levels of PRMT8 are linked to a variety of
cancers [196]. Furthermore, knockdown of PRMT8 halted cell proliferation and
caused cell death in both healthy human dermal fibroblasts and U87MG glioblastoma cells [194].
10.2 Inhibitors: In Vitro and Cell-Based Activities
No specific inhibitors have been developed against PRMT8. Interestingly,
ethylenediamino-containing compounds (fragment 49 [134], MS049 (51) [135],
Fig. 11) that were active against PRMT4 and PRMT6 were also generally active
against PRMT8. In addition, the covalent inhibitors 28 and 29 [91] (Fig. 6) designed
to interact with the active site cysteine found in PRMT1 were also found to be active
against PRMT8. This is not surprising given the high sequence similarity, including
the presence of an active site cysteine, between these two PRMTs.
184
M. J. van Haren and N. I. Martin