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; Jian Huang

doi:10.18632/oncotarget.3105

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

Oncotarget. 2015 Mar 30;6(9):6762-75. doi: 10.18632/oncotarget.3105.

Authors

Bo Liu¹, Leilei Fu¹, Cui Zhang², Lan Zhang², Yonghui Zhang^{1

3}, Liang Ouyang¹, Gu He¹, Jian Huang²

Affiliations

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.

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.

Keywords: ERK inhibitor (BL-EI001); apoptosis; breast cancer; extracellular signal-regulated kinase 1/2 (ERK1/2); mitochondrial pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / toxicity
Apoptosis / drug effects*
Benzothiazoles / chemical synthesis*
Benzothiazoles / pharmacology*
Benzothiazoles / toxicity
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / genetics
Breast Neoplasms / pathology
Cell Proliferation / drug effects
Computer-Aided Design*
Dose-Response Relationship, Drug
Drug Design*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Female
Humans
Imidazoles / chemical synthesis*
Imidazoles / pharmacology*
Imidazoles / toxicity
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Mitochondria / drug effects
Mitochondria / enzymology
Mitochondria / pathology
Molecular Docking Simulation
Molecular Structure
Molecular Targeted Therapy
Phosphorylation
Protein Interaction Maps
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / toxicity
Proteomics
RNA Interference
Signal Transduction / drug effects
Structure-Activity Relationship
Time Factors
Transfection
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
BL-EI001
Benzothiazoles
Imidazoles
Protein Kinase Inhibitors
Extracellular Signal-Regulated MAP Kinases