Integrated bioinformatics, computational and experimental methods to discover novel Raf/extracellular-signal regulated kinase (ERK) dual inhibitors against breast cancer cells

Yin Chen; Yaxin Zheng; Qinglin Jiang; Feifei Qin; Yonghui Zhang; Leilei Fu; Gu He

doi:10.1016/j.ejmech.2016.11.009

Integrated bioinformatics, computational and experimental methods to discover novel Raf/extracellular-signal regulated kinase (ERK) dual inhibitors against breast cancer cells

Eur J Med Chem. 2017 Feb 15:127:997-1011. doi: 10.1016/j.ejmech.2016.11.009. Epub 2016 Nov 8.

Authors

Yin Chen¹, Yaxin Zheng¹, Qinglin Jiang², Feifei Qin¹, Yonghui Zhang³, Leilei Fu⁴, Gu He⁵

Affiliations

¹ State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
² State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; School of Pharmacy and Sichuan Province College Key Laboratory of Structure-Specific Small Molecule Drugs, Chengdu Medical College, Chengdu 610500, China.
³ Collaborative Innovation Center for Biotherapy, School of Medicine, Tsinghua University, Beijing 100084, China.
⁴ State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: leilei_fu@163.com.
⁵ State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: hegu@scu.edu.cn.

PMID: 27839788
DOI: 10.1016/j.ejmech.2016.11.009

Abstract

Beginning with our previously reported ERK inhibitor BL-EI001, we found Raf1 to be an important regulator in the ERK interactive network, and then we designed and synthesized a novel series of Raf1/ERK dual inhibitors against human breast cancers through integrative computational, synthetic and biological screening methods. Moreover, we found that compound 9d suppressed the proliferation of breast cancer cell lines and induced cellular apoptosis via a mitochondrial pathway with only partial dependence on Raf1 and ERK. Our results suggest that an integrative method including in silico design, chemical synthesis, biological screening and bioinformatics analysis could be an attractive strategy for the discovery of multi-target inhibitors against breast cancer.

Keywords: Bioinformatics; Breast cancer; ERK; Kinase inhibitor; Raf.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Breast Neoplasms / pathology*
Computational Biology*
Drug Design
Drug Discovery / methods*
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors*
Extracellular Signal-Regulated MAP Kinases / chemistry
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
MCF-7 Cells
Mitochondria / drug effects
Mitochondria / metabolism
Molecular Docking Simulation
Phosphatidylethanolamine Binding Protein / antagonists & inhibitors*
Phosphatidylethanolamine Binding Protein / chemistry
Phosphatidylethanolamine Binding Protein / metabolism
Protein Domains
Protein Kinase Inhibitors / pharmacology*
Sequence Homology, Amino Acid

Substances

Antineoplastic Agents
Phosphatidylethanolamine Binding Protein
Protein Kinase Inhibitors
Extracellular Signal-Regulated MAP Kinases