Computational design, chemical synthesis, and biological evaluation of a novel ERK inhibitor (BL-EI001) with apoptosis-inducing mechanisms in breast cancer.
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.
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Bo
B
Liu
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Leilei
L
Fu
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Cui
C
Zhang
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Lan
L
Zhang
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.|Collaborative Innovation Center for Biotherapy, Department of Pharmacology & Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
Yonghui
Y
Zhang
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Liang
L
Ouyang
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Gu
G
He
School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China.
Jian
J
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D060066:Protein Interaction Maps; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D040901:Proteomics; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C000604216:BL-EI001; D052160:Benzothiazoles; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases
ERK inhibitor (BL-EI001); apoptosis; breast cancer; extracellular signal-regulated kinase 1/2 (ERK1/2); mitochondrial pathway