MYST proteins are the largest family of Histone acetyltransferases (HATs) and have a conserved MYST domain responsible for the acetyl transferase activity[1]. MOZ-IN-3, also known as WM8013, is a selective inhibitor of KAT6A, KAT6B, KAT5 and KAT7 of MYST with IC50 values of 8nM, 28nM, 224nM and 342nM, respectively. In vitro, MOZ-IN-3 inhibited MEFs proliferate after 10 days of treatment with IC50 value of 2.4nM. Treatment with 10μM MOZ-IN-3 for 6 days increased the proportion of cells in G0/G1 and a corresponding reduction in cells in G2/M and S phases. In addition, MOZ-IN-3 increased the β-galactosidase activity and Cdkn2a mRNA expression. These results showed that MOZ-IN-3 causing cell cycle arrest leading to senescence. Treatment with 10μM MOZ-IN-3 directly inhibited global H3K14 acetylation catalyzed by KAT7, and KAT6A-specific H3K9 acetylation at transcription start sites. MOZ-IN-3 also inhibited the proliferation of B cell lymphoma cell line EMRK1184 with IC50 value of 2.3μM. Treatment with 10μM MOZ-IN-3 potentiated oncogene-induced senescence without affect the growth of the normal hepatocyte in the zebrafish model hepatocellular carcinoma. However, the plasma protein binding of MOZ-IN-3 more was greater than 99.9% precluding in vivo studies in mice[2].
作用机制
MOZ-IN-3 competes directly with acetyl-CoA in the MYST lysine acetyltransferase domain[2].
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