title: IC-4, a new irreversible EGFR inhibitor, exhibits prominent anti-tumor and anti-angiogenesis activities.
abstract: Accumulating evidence suggested that the irreversible tyrosine kinase inhibitors (TKIs) have potential to override the acquired resistance to target-based therapies. Herein, we reported IC-4 as a novel irreversible TKI for epidermal growth factor receptor (EGFR). IC-4 potentially suppressed proliferation, induced apoptosis and a G2/M cell cycle arrest in breast cancer cells, correlating with inhibition of EGF-induced EGFR activation, but independent of DNA damage. In addition, IC-4 exhibited anti-angiogenetic activities both in vitro and in vivo. It suppressed cell viability and proliferation induced by various growth factors in human umbilical vein endothelial cells (HUVECs). IC-4 also inhibited HUVECs migration and tube formation. In transgenic zebrafish embryo model, IC-4 was shown to suppress formation of intersegmental vessel and development of subintestinal vessels. Taken together, these results demonstrated that IC-4 is a new irreversible EGFR-TKI, exhibiting potent anti-breast cancer and anti-angiogenetic effects.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Ying-Bo
authors.initials: YB
authors.lastname: Li
authors.forename: Zhong-Qing
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Yan
authors.forename: Mei-Wan
authors.initials: MW
authors.lastname: Chen
authors.forename: Jiao-Lin
authors.initials: JL
authors.lastname: Bao
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Wu
authors.forename: Ze-Mei
authors.initials: ZM
authors.lastname: Ge
authors.forename: De-Min
authors.initials: DM
authors.lastname: Zhou
authors.forename: Yi-Tao
authors.initials: YT
authors.lastname: Wang
authors.forename: Run-Tao
authors.initials: RT
authors.lastname: Li
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D013859:Thiocarbamates / Q000494:pharmacology*; D015027:Zebrafish
chemical_list: C584447:2-(benzylsulfinyl)ethyl pyridin-3-ylmethylcarbamodithioate; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013859:Thiocarbamates; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Angiogenesis; Breast cancer; EGFR; Irreversible TKI