Research Papers:

Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer

Bo Liu _, Leilei Fu, Cui Zhang, Lan Zhang, Yonghui Zhang, Liang Ouyang, Gu He and Jian Huang

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Oncotarget. 2015; 6:6762-6775. https://doi.org/10.18632/oncotarget.3105

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Bo Liu1, Leilei Fu1, Cui Zhang2, Lan Zhang2, Yonghui Zhang1,3, Liang Ouyang1, Gu He1, Jian Huang2

1State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China

2School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China

3Collaborative Innovation Center for Biotherapy, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China

Correspondence to:

Liang Ouyang, e-mail: [email protected]

Gu He, e-mail: [email protected]

Jian Huang, e-mail: [email protected]

Keywords: Extracellular signal-regulated kinase 1/2 (ERK1/2), ERK inhibitor (BL-EI001), Apoptosis, Mitochondrial pathway, Breast cancer

Received: December 31, 2014     Accepted: January 08, 2015     Published: January 27, 2015


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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