当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives as novel ULK1 inhibitors that block autophagy and induce apoptosis in non-small cell lung cancer.

Discovery of 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives as novel ULK1 inhibitors that block autophagy and induce apoptosis in non-small cell lung cancer.

Abstract：

:UNC51-like kinase1 (ULK1) recruits its binding partners and initiates the autophagy process in cancer. ULK1 is significantly overexpressed in Non-small cell lung cancer (NSCLC) and negatively correlated with clinical prognosis in NSCLC patients. Based upon the binding features of ULK1, we explored the pharmacophore modeling to discover the common anchoring features. It was verified by synthesizing 5-bromo-4-phenoxy-N-phenylpyrimidin-2-amine derivatives, as well as subsequently elucidating the structure-activity relationships (SAR). Among all the obtained ULK1 inhibitors, 5-bromo-4-(2-fluoro-4-nitrophenoxy)-N-(3,4,5-trimethoxyphenyl) pyrimidin-2-amine (3s), was the most active one. The docking analysis was conducted to compare 3s and SBI-0206965, which further elucidated the roles of the H-bond donor. This compound inhibited the proliferation of A549 cells and showed strong inhibitory activity against ULK1 kinase. Moreover, we found that compound 3s could induce apoptosis while simultaneously blocking autophagy. Collectively, these findings shed new light on compound 3s that would be utilized as a promising candidate drug for the future NSCLC therapy.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Sun D,Yang Z,Zhen Y,Yang Y,Chen Y,Yuan Y,Zhang L,Zeng X,Chen L

doi

10.1016/j.ejmech.2020.112782

subject

Has Abstract

pub_date

2020-12-15 00:00:00

pages

112782

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30754-6

journal_volume

208

pub_type

杂志文章

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