title: Integrated bioinformatics, computational and experimental methods to discover novel Raf/extracellular-signal regulated kinase (ERK) dual inhibitors against breast cancer cells.
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.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Qin
authors.affiliation: Collaborative Innovation Center for Biotherapy, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Leilei
authors.initials: L
authors.lastname: Fu
authors.affiliation: 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.
authors.forename: Gu
authors.initials: G
authors.lastname: He
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D019295:Computational Biology; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D049488:Phosphatidylethanolamine Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017386:Sequence Homology, Amino Acid
chemical_list: D000970:Antineoplastic Agents; D049488:Phosphatidylethanolamine Binding Protein; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Bioinformatics; Breast cancer; ERK; Kinase inhibitor; Raf