title: Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer.
abstract: Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor.
authors.affiliation: School of Life Sciences and Key Laboratory of Ministry of Education for Bio-Resources and Bio-Environment, Sichuan University, Chengdu 610064, China. lijianzong@hotmail.com.
authors.forename: Jianzong
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Life Sciences and Key Laboratory of Ministry of Education for Bio-Resources and Bio-Environment, Sichuan University, Chengdu 610064, China. haiyangwang1@outlook.com.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Sciences and Key Laboratory of Ministry of Education for Bio-Resources and Bio-Environment, Sichuan University, Chengdu 610064, China. jimzz@alumni.sjtu.edu.cn.
authors.forename: Junjie
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Life Sciences and Key Laboratory of Ministry of Education for Bio-Resources and Bio-Environment, Sichuan University, Chengdu 610064, China. baojinku@scu.edu.cn.|State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. baojinku@scu.edu.cn.|State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu 610041, China. baojinku@scu.edu.cn.
authors.forename: Jinku
authors.initials: J
authors.lastname: Bao
authors.affiliation: School of Life Sciences and Key Laboratory of Ministry of Education for Bio-Resources and Bio-Environment, Sichuan University, Chengdu 610064, China. wuchuanfang@scu.edu.cn.
authors.forename: Chuanfang
authors.initials: C
authors.lastname: Wu
mesh_terms: D000083:Acetanilides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001665:Binding Sites; D001688:Biological Products / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006801:Humans; D000077341:Lapatinib; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000378:metabolism / Q000493:pharmacokinetics; D012372:ROC Curve; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D001688:Biological Products; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D045162:Thiazolidinediones; C000601359:ZINC17167211; C508053:ERBB2 protein, human
keywords: ADMET (absorption, distribution, metabolism, excretion and toxicity); HER2 (human epidermal growth factor receptor 2); biological evaluation; virtual screening