期刊
ONCOTARGET
卷 6, 期 9, 页码 6762-6775出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3105
关键词
Extracellular signal-regulated kinase 1/2 (ERK1/2); ERK inhibitor (BL-EI001); Apoptosis; Mitochondrial pathway; Breast cancer
资金
- National 973 Basic Research Program of China [2013CB911300]
- Key Projects of the National Science and Technology Pillar Program [2012BAI30B02]
- National Natural Science Foundation of China [81402496, 81473091]
Extracellular signal-regulated kinase1/2 (ERK1/2) plays a crucial role in the resistance of apoptosis in carcinogenesis; however, its targeted small-molecule inhibitors still remain to be discovered. Thus, in this study, we computationally and experimentally screened a series of small-molecule inhibitors targeting ERK toward different types of human breast cancer cells. Subsequently, we synthesized some candidate ERK inhibitors, identified a novel ERK inhibitor (BL-EI001) with anti-proliferative activities, and analyzed the BL-EI001/ERK complex. Moreover, we found that BL-EI001 induced breast cancer cell apoptosis via mitochondrial pathway but independent on Ras/Raf/MEK pathway. In addition, we carried out proteomics analyses for exploring some possible BL-EI001-induced apoptotic pathways, and further found that BL-EI001-induced apoptosis affected ERK phosphorylation in breast cancer. Further, we found that BL-EI001 bear anti-tumor activities without remarkable toxicities, and also induced mitochondrial apoptosis by targeting ERK in vivo. Taken together, these results demonstrate that in silico design and experimental discovery of a synthesized small-molecule ERK inhibitor (BL-EI001) as a potential novel apoptosis-inducing drug in the treatment of breast cancer.
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