Epizyme, Inc., Cambridge, Massachusetts, United States of America.
PLoS One. 2018 Jun 1;13(6):e0197372. doi: 10.1371/journal.pone.0197372. eCollection 2018.
A key challenge in the development of precision medicine is defining the phenotypic consequences of pharmacological modulation of specific target macromolecules. To address this issue, a variety of genetic, molecular and chemical tools can be used. All of these approaches can produce misleading results if the specificity of the tools is not well understood and the proper controls are not performed. In this paper we illustrate these general themes by providing detailed studies of small molecule inhibitors of the enzymatic activity of two members of the SMYD branch of the protein lysine methyltransferases, SMYD2 and SMYD3. We show that tool compounds as well as CRISPR/Cas9 fail to reproduce many of the cell proliferation findings associated with SMYD2 and SMYD3 inhibition previously obtained with RNAi based approaches and with early stage chemical probes.
精准医学发展的一个关键挑战是定义特定靶标大分子的药理学调节的表型后果。为了解决这个问题，可以使用各种遗传、分子和化学工具。如果工具的特异性没有得到很好的理解，并且没有进行适当的对照，那么所有这些方法都可能产生误导性的结果。在本文中，我们通过提供对蛋白质赖氨酸甲基转移酶 SMYD 分支的两个成员 SMYD2 和 SMYD3 的酶活性的小分子抑制剂的详细研究来说明这些一般主题。我们表明，工具化合物以及 CRISPR/Cas9 无法复制以前使用 RNAi 方法和早期化学探针获得的与 SMYD2 和 SMYD3 抑制相关的许多细胞增殖发现。
