Logical design of an anti-cancer agent targeting the plant homeodomain in Pygopus2.
Logical design of an anti-cancer agent targeting the plant homeodomain in Pygopus2.
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DOI：
10.1111/cas.12995
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发表时间：
2016-09
期刊：
影响因子：
5.7
通讯作者：
Kuwata K
中科院分区：
文献类型：
--
作者：
Ali F;Yamaguchi K;Fukuoka M;Elhelaly AE;Kuwata K
Pygopus2 （Pygo2）是Wnt信号通路的一个组成部分，是β - catenin介导的转录所必需的。Pygo2中的植物同源结构域（PHD）手指插入与β -连环蛋白结合的BCL9的甲基化组蛋白3 （H3K4me）尾部和HD1结构域。因此，PHD手指可能是抗癌药物逻辑设计的潜在靶点。本研究发现，名为JBC117的Spiro[2H -萘酚[1,2‐b]吡喃- 2,4′-哌啶]- 1′乙醇，3,4‐二氢- 4‐羟基- α‐（6‐甲基- 1H‐吲哚- 3‐基）)与PHD中与H3K4me和/或HD1结合位点对应的D339、A348、R356、V376和A378相互作用，具有较强的抗癌作用。结肠癌（HCT116）和肺癌（A549）的ic50值分别为2.6±0.16和3.3±0.14 μM，而正常人成纤维细胞的ic50值为33.80±0.15 μM。JBC117能有效拮抗β - catenin依赖活性的细胞效应，并抑制癌细胞的迁移和侵袭。体内研究表明，皮下注射JBC117 （10 mg/kg/天）可显著延长小鼠的存活时间。综上所述，JBC117是一种靶向Pygo2 PHD指的新型抗癌先导化合物，具有治疗结肠癌和肺癌的作用。
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, IC 50 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.
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影响因子：
64.5
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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DOI：
10.1083/jcb.200810133
发表时间：
2009-06-01
期刊：
The Journal of cell biology
影响因子：
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作者：
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Dai X
影响因子：
14.8
作者：
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通讯作者：
Lum, Lawrence