Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7,ChemMedChem

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Structure–Activity Relationship Studies on (R)‐PFI‐2 Analogues as Inhibitors of Histone Lysine Methyltransferase SETD7
ChemMedChem ( IF 3.6 ) Pub Date : 2018-06-25 , DOI: 10.1002/cmdc.201800242
Danny C. Lenstra ₁ , Eddy Damen ₂ , Ruben G. G. Leenders ₂ , Richard H. Blaauw ₃ , Floris P. J. T. Rutjes ₁ , Anita Wegert ₂ , Jasmin Mecinović ₁

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SETD7 is a histone H3K4 lysine methyltransferase involved in human gene regulation. Aberrant expression of SETD7 has been associated with various diseases, including cancer. Therefore, SETD7 is considered a good target for the development of new epigenetic drugs. To date, few selective small‐molecule inhibitors have been reported that target SETD7, the most potent being (R)‐PFI‐2. Herein we report structure–activity relationship studies on (R)‐PFI‐2 and its analogues. A library of 29 structural analogues of (R)‐PFI‐2 was synthesized and evaluated for inhibition of recombinantly expressed human SETD7. The key interactions were found to be a salt bridge and a hydrogen bond formed between (R)‐PFI‐2′s NH₂⁺ group and SETD7′s Asp256 and His252 residue, respectively.

中文翻译：

（R）-PFI-2类似物作为组蛋白赖氨酸甲基转移酶SETD7抑制剂的构效关系研究

SETD7是一种参与人类基因调控的组蛋白H3K4赖氨酸甲基转移酶。SETD7的异常表达与多种疾病有关，包括癌症。因此，SETD7被认为是开发新的表观遗传药物的良好靶标。迄今为止，鲜有报道报道靶向SETD7的选择性小分子抑制剂很少，最有效的是（R）-PFI-2。在此，我们报告了对（R）-PFI-2及其类似物的结构-活性关系研究。合成了（R）-PFI-2的29个结构类似物的文库，并评估了其对重组表达的人SETD7的抑制作用。发现关键的相互作用是盐桥和（R）-PFI-2的NH ₂⁺之间形成氢键组和SETD7的Asp256和His252残基。

更新日期：2018-06-25

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