Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ, Nijmegen, The Netherlands.
Mercachem BV, Kerkenbos 1013, 6546 BB, Nijmegen, The Netherlands.
ChemMedChem. 2018 Jul 18;13(14):1405-1413. doi: 10.1002/cmdc.201800242. Epub 2018 Jun 25.
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 NH group and SETD7's Asp256 and His252 residue, respectively.
SETD7 是一种组蛋白 H3K4 赖氨酸甲基转移酶，参与人类基因调控。SETD7 的异常表达与各种疾病有关，包括癌症。因此，SETD7 被认为是开发新的表观遗传药物的一个很好的靶点。迄今为止，已经报道了几种选择性的小分子抑制剂可以靶向 SETD7，其中最有效的是 (R)-PFI-2。本文报道了 (R)-PFI-2 及其类似物的构效关系研究。合成了 (R)-PFI-2 的 29 个结构类似物库，并对其抑制重组表达的人 SETD7 的活性进行了评价。发现关键的相互作用是 (R)-PFI-2 的 NH 基团与 SETD7 的 Asp256 和 His252 残基之间形成的盐桥和氢键。
