Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation

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（precision medicine）研发过程中的一项核心挑战，在于明确特定靶标大分子经药理学调控后所产生的表型效应。为解决该问题，可采用各类遗传、分子与化学工具。若未能充分明确工具的特异性，且未开展恰当的对照实验，上述所有实验策略均可能得到误导性结果。本文以蛋白质赖氨酸甲基转移酶（protein lysine methyltransferases）SMYD分支的两个成员SMYD2与SMYD3的酶活性小分子抑制剂为研究对象开展详细分析，以此阐明上述通用研究主题。研究表明，工具化合物与CRISPR/Cas9均无法复现此前基于RNA干扰（RNAi）的实验方法及早期化学探针所获得的、与SMYD2和SMYD3抑制相关的多数细胞增殖相关实验结果。