Structural Genomics Consortium, Nuffield Department of Medicine , University of Oxford , OX3 7DQ Oxford , U.K.
Target Discovery Institute, Nuffield Department of Medicine , University of Oxford , OX3 7FZ Oxford , U.K.
J Med Chem. 2019 Oct 24;62(20):9008-9025. doi: 10.1021/acs.jmedchem.9b00562. Epub 2019 Oct 15.
Modifications of histone tails, including lysine/arginine methylation, provide the basis of a "chromatin or histone code". Proteins that contain "reader" domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional coactivator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a role in cancer related inflammation and/or cancer metastasis.
组蛋白尾部的修饰，包括赖氨酸/精氨酸甲基化，为“染色质或组蛋白密码”提供了基础。含有“读取器”结构域的蛋白质可以与这些修饰结合，并形成特定的效应复合物，最终介导染色质功能。Spindlin1 (SPIN1) 蛋白含有三个 Tudor 甲基赖氨酸/精氨酸读取器结构域，被鉴定为潜在的癌基因和转录共激活因子。在这里，我们报告了一种 SPIN1 化学探针抑制剂，它在体外具有低纳摩尔的活性，对一系列甲基读取器和写入器蛋白具有极高的选择性，并且在细胞内具有亚微摩尔的活性。X 射线晶体学显示，这种 Tudor 结构域化学探针通过双齿结合模式同时与 Tudor 结构域 1 和 2 结合。小分子抑制和 SPIN1 的 siRNA 敲低，以及化学蛋白质组学研究，鉴定了 SPIN1 在鳞状细胞癌中转录调控的基因，并表明 SPIN1 可能在癌症相关炎症和/或癌症转移中发挥作用。
