GSK343

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].

References:
[1] Verma S K, Tian X, LaFrance L V, et al.  Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS medicinal chemistry letters, 2012, 3(12): 1091-1096.
[2] Ferraro A, Boni T, Pintzas A.  EZH2 Regulates Cofilin Activity and Colon Cancer Cell Migration by Targeting ITGA2 Gene. PloS one, 2014, 9(12): e115276.
[3] Amatangelo M, Garipov A, Li H, et al.  Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition. Cell Cycle, 2013, 12(13): 2113-2119.
[4] Liu T P, Lo H L, Wei L S, et al.  S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells. Anti-cancer drugs, 2015, 26(2): 139.

In silico and experimental analyses predict the therapeutic value of an EZH2 inhibitor GSK343 against hepatocellular carcinoma through the induction of metallothionein genes.[Pubmed:26973856]

Oncoscience. 2016 Jan 29;3(1):9-20.

There are currently no effective molecular targeted therapies for hepatocellular carcinoma (HCC), the third leading cause of cancer-related death worldwide. Enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27 (H3K27)-specific methyltransferase, has been emerged as novel anticancer target. Our previous study has demonstrated that GSK343, an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2, induces autophagy and enhances drug sensitivity in cancer cells including HCC. In this study, an in silico study was performed and found that EZH2 was overexpressed in cancerous tissues of HCC patients at both gene and protein levels. Microarray analysis and in vitro experiments indicated that the anti-HCC activity of GSK343 was associated with the induction of metallothionein (MT) genes. In addition, the negative association of EZH2 and MT1/MT2A genes in cancer cell lines and tissues was found in public gene expression database. Taken together, our findings suggest that EZH2 inhibitors could be a good therapeutic option for HCC, and induction of MT genes was associated with the anti-HCC activity of EZH2 inhibitors.

Fuse-binding protein 1 is a target of the EZH2 inhibitor GSK343, in osteosarcoma cells.[Pubmed:27278257]

Int J Oncol. 2016 Aug;49(2):623-8.

Osteosarcoma is the primary cancer of leaf tissue and is regarded as a differentiation disease caused by genetic and epigenetic changes which interrupt the osteoblast differentiation from mesenchymal stem cells. Because of its high malignancy degree and rapid development, the morbidity and mortality are high. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of polycomb repressive complex 2 (PRC2) and has been demonstrated to be involved in a variety of biological processes, such as cell proliferation and program cell death. EZH2 impairs gene expression by catalyzing the tri-methylation of histone H3 lysine 27 (H3K27me3) which controls gene transcription epigenetically. It is reported that EZH2 expression is higher in osteosarcoma than in osteoblastoma and the highest expression of EZH2 is found in osteosarcoma with metastasis. In the past few years, several potent inhibitors of EZH2 have been discovered, and GSK343 is one of them. In this study, we found that GSK343 inhibited osteosarcoma cell viability, restrained cell cycle transition and promoted programmed cell death. GSK343 not only inhibited the expression of EZH2 and its target, c-Myc and H3K27me3, but it also inhibited fuse binding protein 1 (FBP1) expression, another c-Myc regulator. Furthermore, we found that FBP1 physically interacts with EZH2. Based on these results, we believe that GSK343 is a potential molecule for osteosarcoma clinical treatment. Other than the inhibition on EZH2-c-Myc signal pathway, we postulate that the inhibition on FBP1-c-Myc signal pathway is another potential underlying mechanism with which GSK343 inhibits osteosarcoma cell viability.