Histone acetyltransferases (HATs) play a vital role in a range of epigenetic pathways by the acetylation of histones using acetyl-CoA as substrate. MYST family is responsible for a wide range of cellular events and comprising approximately one-third in the human genome. WM-119 is a selective inhibitor of KAT6A of MYST[1]. WM119 can bind to KAT6A, KAT5 and KAT7 at a binding KD values of 2 nM, 2.2 μM and 0.5 μM, respectively. In vitro, treatment with WM-1119 resulted in increased levels of Cdkn2a and Cdkn2b mRNA and P16 and P19 proteins, as well as a delayed increase in Cdkn1a mRNA. WM-1119 inhibited the proliferation of B cell lymphoma cell line EMRK1184 with IC50 value of 0.25 μM. Treatment of mouse embryonic fibroblasts (MEFs) with 1 μM WM-1119 induced cell cycle arrest in G1 and a senescence phenotype. In vivo, administered WM-1119 at 50 mg/kg via intraperitoneal injection four times daily for 14 days substantially reduced the level of H3K9ac in lymphoma cells, and the proportion and overall number of lymphoma cells in mice, suggesting that WM-1119 was effective in treating lymphoma in vivo[2].
作用机制
M-1119 competes with acetyl-CoA in the MYST lysine acetyltransferase domain[2].
搜索
