title: Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: design, synthesis, and biological activity.
abstract: A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme-linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure-activity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2-5) are potent inhibitors of FGFR1 with IC(50) values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC(50) values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).
authors.affiliation: School of Pharmacy, East China University of Science and Technology , Shanghai, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhu
authors.forename: Xianwen
authors.initials: X
authors.lastname: Cao
authors.forename: Linjiang
authors.initials: L
authors.lastname: Tong
authors.forename: Honglin
authors.initials: H
authors.lastname: Li
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Yufang
authors.initials: Y
authors.lastname: Xu
authors.forename: Shaoying
authors.initials: S
authors.lastname: Tan
authors.forename: Dong
authors.initials: D
authors.lastname: Kuang
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Xuhong
authors.initials: X
authors.lastname: Qian
mesh_terms: D000073:Acenaphthenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006041:Goats; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000073:Acenaphthenes; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C560274:ethyl 8-oxo-8H-acenaphtho(1,2-b)pyrrole-9-carboxylate; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases