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Cancer Sci. 2016 Sep;107(9):1321-8. doi: 10.1111/cas.12995. Epub 2016 Aug 16.

Logical design of an anti-cancer agent targeting the plant homeodomain in Pygopus2.

Author information

1
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
2
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan. kuwata@gifu-u.ac.jp.
3
Department of Gene and Development, Graduate School of Medicine, Gifu University, Gifu, Japan. kuwata@gifu-u.ac.jp.

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.

KEYWORDS:

Pygopus2; Wnt; logical drug design; plant homeodomain; β-catenin

PMID:
27324116
PMCID:
PMC5021024
DOI:
10.1111/cas.12995
[Indexed for MEDLINE]
Free PMC Article

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