化学
T790米
表皮生长因子受体
表皮生长因子受体抑制剂
自噬
小分子
酪氨酸激酶
细胞凋亡
细胞周期检查点
细胞生长
细胞培养
信号转导
癌症研究
细胞周期
药理学
受体
吉非替尼
生物化学
生物
遗传学
作者
Hongyi Zhao,Xueyan Yang,Hao Lei,Xiao-Xiao Xi,Shemin Lu,Junjie Zhang,Minhang Xin,San‐Qi Zhang
标识
DOI:10.1016/j.ejmech.2020.112781
摘要
Epidermal growth factor receptor (EGFR) is an important therapeutic target for the treatment of non-small cell lung cancer. A number of efficacious EGFR tyrosine kinase inhibitors have been developed. However, acquired drug resistance largely encumbered their clinical practicability. Therefore, there is an urgent need to develop new therapeutic regime. Herein, we designed and synthesized a set of EGFR-targeting small molecule PROTACs which showed promising efficacy. In particular, VHL-recruiting compound P3 showed potent anti-proliferative activity against HCC827 and H1975 cell lines with IC50 values of 0.83 and 203.01 nM, respectively. Furthermore, both EGFRdel19 and EGFRL858R/T790M could be significantly induced to be degraded under treatment of P3 with DC50 values of 0.51 and 126.2 nM, respectively. Compound P3 was able to dramatically suppress EGFR pathway signal transduction. Moreover, compound P3 could significantly induce cell apoptosis, arrest cell cycle and suppress cell colony formation. In addition, we identified that ubiquitination was indispensable in the degradation process, and found that the degradation was related to autophagy. Our work would provide an alternative approach for development of potentially effective EGFR degraders and give a new clue for investigation of PROTAC-induced protein degradation.
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