化学
癌症研究
异羟肟酸
蛋白激酶B
突变体
表皮生长因子受体抑制剂
细胞培养
ErbB公司
T790米
细胞生长
生物化学
表皮生长因子受体
吉非替尼
磷酸化
立体化学
信号转导
生物
受体
基因
遗传学
作者
Lei Zhao,Tingting Fan,Zhichao Shi,Chao Ding,Cunlong Zhang,Zigao Yuan,Qiao Sun,Chunyan Tan,Binbin Chu,Yuyang Jiang
标识
DOI:10.1016/j.ejmech.2021.113173
摘要
Acquired resistance leads to the failure of EGFR TKIs in NSCLC treatment. A novel series of hydroxamic acid-containing 4-aminoquinazoline derivatives as irreversible ErbB/HDAC multitargeted inhibitors for NSCLC therapy had been designed and synthesized, which displayed weak anti-proliferative activity in several EGFR wild-type cancer cell lines (NCI–H838, SK-BR-3, A549, A431) yet retained moderate activity to EGFRT790M resistance mutation harboring NCI–H1975 cells. The mechanistic studies revealed that the representative compound 11e was able to inhibit the phosphorylation of EGFR, up-regulate hyperacetylation of histone H3 and even reduce the expression of EGFR and Akt in NCI–H1975 cells. In further assays, compound 11e also showed moderate anti-proliferative activity in other EGFRT790M harboring tumor cell lines (NCI–H820, Ba/F3_EGFR_Del19-T790M-C797S) and low toxicities in normal cell lines (HL-7702, FHC). This selectivity of designed multitargeted compounds could serve as a potential strategy to circumvent multiple mechanisms of acquired resistance to EGFR-targeted therapy without severe toxicities and side effects resulting from broad inhibition.
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