T790米
化学
药理学
奥西默替尼
喹唑啉
铅化合物
体外
癌症研究
生物化学
立体化学
表皮生长因子受体
受体
医学
埃罗替尼
吉非替尼
作者
Yangming Guo,Biao Gao,Peng Gao,Yuanjiang Wang,Shaohua Gou
标识
DOI:10.1016/j.bmc.2023.117338
摘要
Owing to the urgency and importance of developing fourth-generation EGFR inhibitors that can effectively overcome C797S site mutation in NSCLC, Brigatinib was used in this work as a lead compound to modify its structure to obtain a series of phosphoroxy quinazoline derivatives. Biological study indicated that the inhibitory activity and selectivity of the target compounds on EGFRL858R/T790M/C797S/EGFRDel19/T790M/C797S enzymes and EGFRDel19/T790M/C797S overexpressed Ba/F3 cells were significantly better than those of Brigatinib. Among the target compounds, 8a exhibited the best biological activity in vitro. More importantly, 8a presented acceptable pharmacokinetic behaviors and showed potent anti-tumor efficacy in the Ba/F3-EGFRDel19/T790M/C797S subcutaneous xenograft mice model with the tumor growth inhibition value of 82.60% at a dose of 30 mg/kg. These results indicated that 8a, as a drug candidate of the novel fourth-generation EGFR small-molecule inhibitor, has high potentials to treat with NSCLC on EGFR with C797S mutation.
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