Logical design of an anti‐cancer agent targeting the plant homeodomain in Pygopus2. Issue 9 (16th August 2016)

• Record Type: Journal Article
• Authors: Ali, Ferdausi; Yamaguchi, Keiichi; Fukuoka, Mayuko; Elhelaly, Abdelazim Elsayed; Kuwata, Kazuo
• Is Part Of: Cancer science. Volume 107:Issue 9(2016)
• Page Start: 1321
• Page End: 1328
• Publication Date: 2016-08-16
• Subjects: β‐catenin -- logical drug design -- plant homeodomain -- Pygopus2 -- Wnt; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.12995
• Languages: English
• ISSNs: 1347-9032

Abstract

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[2 H ‐naphthol[1, 2‐ b ]pyran‐2, 4′‐piperidine]‐1′ethanol, 3, 4‐dihydro‐4‐hydroxy‐α‐(6‐methyl‐1 H ‐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. Abstract : We found a novel lead compound, JBC117 that specifically binds with the PHD finger of Pygopus2, a component of the Wnt signaling pathway and has a therapeutic effect against colon and lung cancer. We also found that the survival time of mice bearing cancer xenograft was significantly prolonged by JBC117.