The methyl-lysine reader protein SPIN1 plays important roles in various human diseases. However, targeting methyl-lysine reader proteins has been challenging. Very few cellularly active SPIN1 inhibitors have been developed. We previously reported that our G9a/GLP inhibitor UNC0638 weakly inhibited SPIN1. Here, we present our comprehensive structure–activity relationship study that led to the discovery of compound 11, a dual SPIN1 and G9a/GLP inhibitor, and compound 18 (MS8535), a SPIN1 selective inhibitor. We solved the cocrystal structure of SPIN1 in complex with 11, confirming that 11 occupied one of the three Tudor domains. Importantly, 18 displayed high selectivity for SPIN1 over 38 epigenetic targets, including G9a/GLP, and concentration dependently disrupted the interactions of SPIN1 and H3 in cells. Furthermore, 18 was bioavailable in mice. We also developed 19 (MS8535N), which was inactive against SPIN1, as a negative control of 18. Collectively, these compounds are useful chemical tools to study biological functions of SPIN1.

中文翻译：

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发现一种有效的、选择性的、细胞活性的 SPIN1 抑制剂

甲基赖氨酸阅读蛋白SPIN1在多种人类疾病中发挥着重要作用。然而，针对甲基赖氨酸读取蛋白一直具有挑战性。目前已开发出的细胞活性 SPIN1 抑制剂非常少。我们之前报道过我们的 G9a/GLP 抑制剂 UNC0638 弱抑制 SPIN1。在这里，我们介绍了我们全面的构效关系研究，该研究导致了化合物11（一种 SPIN1 和 G9a/GLP 双重抑制剂）和化合物18 (MS8535)（一种 SPIN1 选择性抑制剂）的发现。我们解析了 SPIN1 与11复合物的共晶结构，证实11占据了三个 Tudor 结构域之一。重要的是，与包括 G9a/GLP 在内的 38 个表观遗传靶标相比， 18 个对 SPIN1 显示出高选择性，并且浓度依赖性地破坏细胞中 SPIN1 和 H3 的相互作用。此外，18在小鼠体内具有生物利用度。我们还开发了19 (MS8535N)，它对 SPIN1 没有活性，作为18的阴性对照。总的来说，这些化合物是研究 SPIN1 生物学功能的有用化学工具。