Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors,Journal of Medicinal Chemistry

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Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2022-06-15 , DOI: 10.1021/acs.jmedchem.2c00709
Na Li _{1,

2} , Hong Yang ₃ , Ke Liu ₄ , Liwei Zhou ₁ , Yuting Huang ₃ , Danyan Cao ₁ , Yanlian Li ₁ , Yaoliang Sun ₅ , Aisong Yu ₃ , Zhiyan Du ₁ , Feng Yu ₄ , Ying Zhang ₃ , Bingyang Wang ₅ , Meiyu Geng _{3,

6} , Jian Li ₇ , Bing Xiong _{1,

2} , Shilin Xu ₅ , Xun Huang _{3,

6} , Tongchao Liu ₁

Affiliation

Overexpression, point mutations, or translocations of protein lysine methyltransferase NSD2 occur in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of multiple domains including a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted in a potent inhibitor 38, which has high selectivity toward the NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition and pave the way to develop potential drugs targeting NSD2 protein.

中文翻译：

基于结构的一系列 NSD2-PWWP1 抑制剂的发现

蛋白质赖氨酸甲基转移酶 NSD2 的过表达、点突变或易位发生在许多类型的癌细胞中。因此，它被认为是一种癌蛋白，被认为是一种很有前途的抗癌药物靶点。NSD2 由多个结构域组成，包括一个 SET 催化结构域和两个与甲基化组蛋白结合的 PWWP 结构域。在这里，我们报告了我们开发一系列 NSD2-PWWP1 抑制剂的努力，进一步基于结构的优化产生了一种有效的抑制剂38，它对 NSD2-PWWP1 结构域具有高选择性。详细的生物学评估表明，化合物38可以与 NSD2-PWWP1 结合，进而影响 NSD2 调控的基因的表达。目前的发现将为未来的研究提供有用的化学探针，以了解PWWP1识别对NSD2的特定调控模式，并为开发靶向NSD2蛋白的潜在药物铺平道路。

更新日期：2022-06-15

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