Small molecule inhibitors of histone acetyltransferase Tip60.
Small molecule inhibitors of histone acetyltransferase Tip60.
复制标题
组蛋白乙酰转移酶 Tip60 的小分子抑制剂。
DOI：
10.1016/j.bioorg.2010.11.003
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发表时间：
2011
影响因子：
5.1
通讯作者：
Zheng,YGeorge
中科院分区：
文献类型：
--
作者：
Wu,Jiang;Wang,Juxian;Li,Minyong;Yang,Yutao;Wang,Binghe;Zheng,YGeorge
Tip60是组蛋白乙酰转移酶MYST家族的关键成员，并参与广谱的细胞途径和疾病状况。迄今为止，Tip60等MYST HAT家族成员的小分子抑制剂的报道很少。为了发现Tip60的新的小分子抑制剂作为功能研究的机械工具和作为治疗开发的化学先导，我们使用Esa 1（Tip60的酵母同系物）的晶体结构在小分子文库数据库上进行虚拟筛选。进行放射性乙酰化测定以进一步评价虚拟筛选命中。从生物化学研究中确定了具有新结构支架的几种化合物对Tip60具有微摩尔抑制效力。此外，计算机建模和动力学分析表明，这些分子的目标乙酰辅酶A结合位点Tip60。这些新的抑制剂为开发MYST HAT的进一步有效抑制剂提供了有价值的化学命中。
Tip60 is a key member of the MYST family of histone acetyltransferases and involved in a broad spectrum of cellular pathways and disease conditions. So far, small molecule inhibitors of Tip60 and other members of MYST HATs are rarely reported. To discover new small molecule inhibitors of Tip60 as mechanistic tools for functional study and as chemical leads for therapeutic development, we performed virtual screening using the crystal structure of Esa1 (the yeast homolog of Tip60) on a small molecule library database. Radioactive acetylation assays were carried out to further evaluate the virtual screen hits. Several compounds with new structural scaffolds were identified with micromolar inhibition potency for Tip60 from the biochemical studies. Further, computer modeling and kinetic assays suggest that these molecules target the acetyl-CoA binding site in Tip60. These new inhibitors provide valuable chemical hits to develop further potent inhibitors for the MYST HATs.