This probe is a dual inhibitor of EZH1 and EZH2 methyltransferase enzymes (in vitro IC50s are 45 nM and 4.6 nM, respectively), which are the components of Polycomb repressive complex 2. This complex converts dimethylated lysines into trimethylated lysines in H3K27. Trimethylation of K27 is a transcriptionally repressive epigenetic mark. The probe inhibits H3K27 trimethylation in MCF10A cells at 5 uM after 3 days treatment, shows toxicity after 7 days of treatment. Potential off-target effects could be due to the GPCR binding with Ki 4,700 nM; 65 nM; 300 nM; and 1,500 nM for Sigma1, Sigma 2, Histamine H3, and Norephedrine transporter, respectively. In vivo studies have shown that the probe has good PK properties; however, its inhibitory effect on EZH1 and EZH2 in different tissues has not been examined, and its organ and tissue distribution profiles were not reported. Therefore, if this probe is used for in vivo studies, careful investigation of its tissue and organ distribution are needed, as well as an analysis of its inhibitory effect of EZH1/2 and off-target GPCR receptors. I recommend using this probe along with UNC2400, which is a negative control molecule.
17 May 2016 )