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GSK343 is a selective and SAM-competitive inhibitor of the histone lysine methyltransferase EZH2 with IC50 value of 4 nM [1].

EZH2 (enhancer of zestehomolog 2) is a catalytic subunit of the protein complex (polycomb repressive complex 2, PRC2). It catalyzes the methylation of H3K27 through transferring the methyl group of SAM to H3K27. The trimethylation of H3K27 subsequently results in the transcription suppression of target genes such as RUNX3, FOXC1 and BRCA1. The overexpression and mutation of EZH2 have been found in many sorts of tumors demonstrating that EZH2 is an attractive target for the treatment of cancers. As a potent EZH2 inhibitor, GSK343 inhibits the activity of the enzyme via competing with the cofactor SAM [1, 2].

GSK343 is a selective EZH2 inhibitor. It showed no significant inhibitory effects on other enzymes requiring SAM as cofactor, including DNMT, MLL, PRMT and SETMAR. GSK343 exerted a certain degree of effective on EZH1 with IC50 value of 240 nM since EZH1 was quite homologous to EZH2. In cultured HCC1806 breast cancer cells, treatment of GSK343 dose-dependently reduced H3K27me3 with IC50 value of 174 nM. Besides that, GSK343 was found to inhibit cell proliferation in some breast and prostate cancer cells. In LNCaP cells, GSK343 suppressed cell growth with IC50 value of 2.9 μM. In human EOC cells, GSK343 notably inhibited cell invasion and induced cell apoptosis. GSK343 was also found to induce LC3-II accumulation and autophagy in A549, MDA-MB-231 and HepG2 cell. It enhanced the antitumor activity of sorafenib which was a multikinase inhibitor and could decrease the expression of EZH2 in HepG2 cells [1, 3 and 4].

GSK343 is only used as a tool to investigate EZH2 in vitro because of its high clearance in the animal model [1].

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