Histone lysine methyltransferases G9a and GLP are validated targets for the development of new epigenetic drugs. Most, if not all, inhibitors of G9a and GLP target the histone substrate binding site or/and the S-adenosylmethionine cosubstrate binding site. Here, we report an alternative approach for inhibiting the methyltransferase activity of G9a and GLP. For proper folding and enzymatic activity, G9a and GLP contain structural zinc fingers, one of them being adjacent to the S-adenosylmethionine binding site. Our work demonstrates that targeting these labile zinc fingers with electrophilic small molecules results in ejection of structural zinc ions, and consequently inhibition of the methyltransferase activity. Very effective Zn(II) ejection and inhibition of G9a and GLP was observed with clinically used ebselen, disulfiram and cisplatin.

组蛋白赖氨酸甲基转移酶G9a和GLP是新表观遗传药物开发的有效靶标。大多数（如果不是全部）G9a和GLP抑制剂靶向组蛋白底物结合位点或/和S-腺苷甲硫氨酸共底物结合位点。在这里，我们报告了另一种抑制G9a和GLP的甲基转移酶活性的方法。为了适当的折叠和酶促活性，G9a和GLP含有结构性锌指，其中之一与S-腺苷甲硫氨酸结合位点相邻。我们的工作表明，用亲电子小分子靶向这些不稳定的锌指会导致结构性锌离子的排出，从而抑制了甲基转移酶的活性。临床上使用依ebselen，diulfiram和cisplatin观察到非常有效的Zn（II）喷射并抑制G9a和GLP。