产品描述:
EPZ-6438 is a potent orally bioavailable, selective inhibitor of the lysine methyltransferase EZH2 (Ki = 2.5nM), the enzymatic subunit of polycomb repressive complex 2 (PRC2) catalyzing the methylation of lysine 27 of histone H3 (H3K27). EPZ-6438 competitively binds to the S-adenosylmethionine (SAM) binding site of EZH2 and non-competitively to the binding sites of peptide or nucleosome substrate. It shows also in vitro potency for EZH2 mutations (Y641F, C, H, N, S and A677G). PRC2 is the only protein methyltransferase that can methylate H3K27 and H3K27 is the only significant substrate for PRC2. Aberrant trimethylation of H3K27 is oncogenic in a broad spectrum of human cancers such as B cell NHL. EPZ-6438 blocks histone H3 lysine 27 trimethylation in both wild-type and mutant lymphoma cells (IC50 range from 2-90nM). EPZ-6438 selectively inhibits EZH2 with selectivity 35-fold greater than EZH1 and >4,500-fold to other histone methyl transferases, including G9a, GLP, SETD7, SMYD2, SMYD3, MMSET, WHSC1L1, PRMTs, DOT1L. EPZ-6438 has potent anticancer properties. It is potent in cellular antiproliferation assays (IC50 ~100nM), inducing apoptosis and differentiation specifically in SMARCB1-deleted malignant rhabdoid tumor (MRT) cells promoting their regression in xenograft-bearing mice. EPZ-6438 has been shown to have anti-neuroinflammatory properties by modulating interferon regulatory factor (IRF) 1, IRF8 and signal transducer and activator of transcription (STAT) 1 levels. EPZ-6438 inhibitors induced anti-inflammatory effects (reducing expression levels of IL-6, IL-1beta, IFN-gamma, TGFbeta and CTGF for inflammation) in liver tissues and may represent a promising target in the treatment of non-alcoholic steatohepatitis (NASH), a progressive disease of NAFLD which leads to fibrosis, cirrhosis and hepatocellular carcinoma. Latent HIV reservoirs are resting immune cells that are infected with HIV but not actively producing HIV. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy (ART) can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive. Inhibition of EZH2 by EPZ-6438, in a model of HIV latency on immune cells isolated from HIV-1-infected patients receiving highly active antiretroviral therapy, induced the reactivation of latent proviruses and might be an approach of reversing latency in HIV.