Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2,Journal of Medicinal Chemistry

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Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-04 , DOI: 10.1021/acs.jmedchem.4c00639
Jianwei Wei ₁ , Qiongyu Shi ₂ , Bang Li ₁ , Hong Yang ₂ , Li Liu ₁ , Ruilin Zhou _{2,

3} , Zongbo Feng ₁ , Zhenjiao Yang ₁ , Jinhong Zhan ₁ , Xiao-Feng Xiong _{1,

4} , Xun Huang _{2,

5} , Yuanxiang Wang _{1,

4}

Affiliation

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

中文翻译：

发现一种靶向赖氨酸甲基转移酶 NSD2 的高效选择性抑制剂

组蛋白赖氨酸甲基转移酶 NSD2 已被公认为癌症治疗的有吸引力的靶标，因为其失调在许多癌症的发生和进展中具有功能意义。尽管已经为开发 NSD2 小分子抑制剂付出了相当大的努力，但到目前为止，高效和选择性的抑制剂仍然很少可用。在这里，我们报告了通过对化合物 8 中特权喹唑啉支架的广泛 SAR 探索发现了一系列新型 NSD2 抑制剂。最有前途的化合物 42 在细胞中表现出优异的 NSD2 酶抑制活性和良好的抗增殖活性。此外，它在 RS411 肿瘤异种移植模型中表现出良好的药代动力学特性并显着抑制肿瘤生长，具有良好的安全性。综上所述，化合物 42 可能是一种很有前途的 NSD2 抑制剂，值得进一步研究。

更新日期：2024-09-04

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