Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC).,European Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › Eur. J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC).
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-01-14 , DOI: 10.1016/j.ejmech.2020.112061
Hao Zhang ₁ , Hong-Yi Zhao ₁ , Xiao-Xiao Xi ₁ , Yan-Jie Liu ₁ , Minhang Xin ₁ , Shuai Mao ₁ , Jun-Jie Zhang ₂ , A-Xin Lu ₃ , San-Qi Zhang ₁

Affiliation

Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC50 values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G1 phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFRdel19-targeting degraders in HCC827 cells. v.

中文翻译：

通过靶向嵌合体的蛋白水解（PROTAC）发现有效的表皮生长因子受体（EGFR）降解剂。

表皮生长因子受体（EGFR）是HER家族的成员，与多种癌症的发生密切相关。在此，我们报告了基于蛋白水解靶向嵌合体（PROTAC）策略的小分子EGFR降解剂的发现。在本研究中，设计并合成了13个含有吡啶并[3,4-d]嘧啶部分的EGFR降解物。有前景的PROTAC 2和10在HCC827细胞中诱导EGFR降解，DC50值分别为45.2和34.8 nM。细胞蛋白控制机制泛素蛋白酶体系统（UPS）参与了降解过程。此外，降解物2和10可以显着诱导HCC827细胞凋亡，并将其停滞在G1期。这些发现表明，化合物2和10可以作为HCC827细胞中靶向EGFRdel19的有效降解剂。

更新日期：2020-01-14

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南