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

// Bo Liu 1 , Leilei Fu 1 , Cui Zhang 2 , Lan Zhang 2 , Yonghui Zhang 1, 3 , Liang Ouyang 1 , Gu He 1 , Jian Huang 2 1 State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China 3 Collaborative Innovation Center for Biotherapy, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China Correspondence to: Liang Ouyang, e-mail: ouyangliang@scu.edu.cn Gu He, e-mail: heguscu@163.com Jian Huang, e-mail: 13504051049@163.com 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 ABSTRACT 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.