RRC ID 63457
Author Ali F, Yamaguchi K, Fukuoka M, Elhelaly AE, Kuwata K.
Title Logical design of an anti-cancer agent targeting the plant homeodomain in Pygopus2.
Journal Cancer Sci
Abstract Pygopus2 (Pygo2) is a component of the Wnt signaling pathway, which is required for β-catenin mediated transcription. Plant homeodomain (PHD) finger in Pygo2 intercalates the methylated histone 3 (H3K4me) tail and HD1 domain of BCL9 that binds to β-catenin. Thus, PHD finger may be a potential target for the logical design of an anti-cancer drug. Here, we found that Spiro[2H-naphthol[1,2-b]pyran-2,4'-piperidine]-1'ethanol,3,4-dihydro-4-hydroxy-α-(6-methyl-1H-indol-3-yl)) termed JBC117 interacts with D339, A348, R356, V376 and A378 in PHD corresponding to the binding sites with H3K4me and/or HD1, and has strong anti-cancer effects. For colon (HCT116) and lung (A549) cancer cell lines, IC50 values were 2.6 ± 0.16 and 3.3 ± 0.14 μM, respectively, while 33.80 ± 0.15 μM for the normal human fibroblast cells. JBC117 potently antagonized the cellular effects of β-catenin-dependent activity and also inhibited the migration and invasion of cancer cells. In vivo studies showed that the survival time of mice was significantly prolonged by the subcutaneous injection of JBC117 (10 mg/kg/day). In conclusion, JBC117 is a novel anti-cancer lead compound targeting the PHD finger of Pygo2 and has a therapeutic effect against colon and lung cancer.
Volume 107(9)
Pages 1321-8
Published 2016-9-1
DOI 10.1111/cas.12995
PMID 27324116
PMC PMC5021024
MeSH Animals Antineoplastic Agents / chemistry* Antineoplastic Agents / pharmacology Cell Line, Tumor Cell Movement / drug effects Disease Models, Animal Drug Design* Female Homeodomain Proteins / antagonists & inhibitors Homeodomain Proteins / chemistry* Humans Intracellular Signaling Peptides and Proteins / antagonists & inhibitors Intracellular Signaling Peptides and Proteins / chemistry* Mice, Nude Models, Molecular Molecular Conformation Nuclear Magnetic Resonance, Biomolecular Protein Binding Protein Interaction Domains and Motifs* Surface Plasmon Resonance Xenograft Model Antitumor Assays beta Catenin / chemistry beta Catenin / metabolism
IF 4.966
Human and Animal Cells A549(RCB0098)