title: Discovery of ERBB3 inhibitors for non-small cell lung cancer (NSCLC) via virtual screening.
abstract: As a member of the epidermal growth factor receptor family (EGFR) of receptor tyrosine kinases, ERBB3 plays an important role in mediating cellular growth and differentiation. Recent research works identified that CD74-NRG1 fusions lead to overexpression of the EGF-like domain of NRG1, and thus activate ERBB3 and PI3K-AKT signaling pathways. The fusion was detected in lung adenocarcinomas, and served as an important oncogenic factor for ERBB3 driven cancers. A sequential virtual screening strategy has been applied to ERBB3 crystal structure using databases of natural products and Chinese traditional medicine compounds, and led to identification of a group of small molecular compounds potentially capable of blocking ERBB3. Six small molecular compounds were selected for in vitro analysis. Five of these molecules significantly inhibited the growth of A549 cells. Among them, compound VS1 is the most promising one with IC50 values of 269.75 μM, comparing to the positive control of nimustine hydrochloride with IC50 values of 264.14 μM. With good specificity and predicted ADMET results, our results support the feasibility by using a pharmacophore of the compound VS1 for designing and optimization of ERBB3 inhibitors.
authors.affiliation: Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.affiliation: Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Li
authors.affiliation: Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China.
authors.forename: Xinrui
authors.initials: X
authors.lastname: Song
authors.affiliation: Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China.
authors.forename: Da
authors.initials: D
authors.lastname: Li
authors.affiliation: Beijing Computing Center, NO.7 Fengxian Middle St, Haidian District, Beijing, 100094, China. zhaoyong@bcc.ac.cn.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000072283:A549 Cells; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D020893:Receptor, ErbB-3
keywords: ERBB3; NRG1; Virtual screening