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

Journal: European journal of medicinal chemistry 2017;127():997-1011

PMID: 27839788

Full Text on Elsevier Science View on PubMed

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.

Address: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.; 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.; Collaborative Innovation Center for Biotherapy, School of Medicine, Tsinghua University, Beijing 100084, China.; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].; State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: [email protected].

DOI: 10.1016/j.ejmech.2016.11.009