The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase
The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase
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Tankyrase靶向Wnt/β-Catenin通路抑制剂K-756的发现及性质研究
DOI：
10.1158/1535-7163.mct-15-0938
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发表时间：
2016-07-01
影响因子：
5.7
通讯作者：
Asai, Akira
中科院分区：
文献类型：
--
作者：
Okada-Iwasaki, Ryoko;Takahashi, Yuichi;Asai, Akira
Wnt/β-连环蛋白途径是一种众所周知的致癌途径。长期以来，它的抑制一直被认为是治疗癌症患者的一个重要挑战。特别是在结肠癌患者中，大多数患者携带导致Wnt/β-连环蛋白通路畸变的腺瘤性结肠息肉病（APC）突变。为了发现Wnt/β-catenin通路的小分子抑制剂，我们使用转录报告基因测定在APC突变结肠癌DLD-1细胞中进行高通量筛选，其鉴定了选择性Wnt/β-catenin通路抑制剂K-756。K-756稳定Axin并减少活性β-连环蛋白，并抑制内源性Wnt/β-连环蛋白下游基因。我们随后确定K-756是端锚聚合酶（TNKS）抑制剂。TNKS属于PARP家族，聚ADP核糖基化Axin并通过蛋白酶体途径促进Axin降解。K-756与TNKS的诱导口袋结合并抑制其酶活性。此外，PARP家族酶测定显示K-756是选择性TNKS抑制剂。K-756通过抑制Wnt/β-catenin通路抑制APC突变型结肠直肠癌科洛320 DM和SW 403细胞的生长。一项体内研究表明，K-756经口给药可抑制小鼠结肠癌异种移植物中的Wnt/β-连环蛋白通路。为了进一步探索K-756的治疗潜力，我们还评估了K-756在非小细胞肺癌细胞中的作用。尽管K-756单次治疗并未诱导抗增殖活性，但当K-756与EGFR抑制剂（吉非替尼）联合使用时，它表现出较强的协同作用。因此，K-756作为一种新型的选择性TNKS抑制剂，有望成为开发抗肿瘤药物的先导化合物。(C)2016年AACR。
The Wnt/beta-catenin pathway is a well-known oncogenic pathway. Its suppression has long been considered as an important challenge in treating cancer patients. Among colon cancer patients in particular, most patients carry an adenomatous polyposis coli (APC) mutation that leads to an aberration of Wnt/beta-catenin pathway. To discover the small molecule inhibitors of the Wnt/beta-catenin pathway, we conducted high-throughput screening in APC-mutant colon cancer DLD-1 cells using a transcriptional reporter assay, which identified a selective Wnt/beta-catenin pathway inhibitor, K-756. K-756 stabilizes Axin and reduces active beta-catenin, and inhibits the genes downstream of endogenous Wnt/beta-catenin. We subsequently identified that K-756 is a tankyrase (TNKS) inhibitor. TNKS, which belongs to the PARP family, poly-ADP ribosylates Axin and promotes Axin degradation via the proteasome pathway. K-756 binds to the induced pocket of TNKS and inhibits its enzyme activity. Moreover, PARP family enzyme assays showed that K-756 is a selective TNKS inhibitor. K-756 inhibited the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/beta-catenin pathway. An in vivo study showed that the oral administration of K-756 inhibited the Wnt/beta-catenin pathway in colon cancer xenografts in mice. To further explore the therapeutic potential of K-756, we also evaluated the effects of K-756 in non-small cell lung cancer cells. Although a single treatment of K-756 did not induce antiproliferative activity, when K-756 was combined with an EGFR inhibitor (gefitinib), it showed a strong synergistic effect. Therefore, K-756, a novel selective TNKS inhibitor, could be a leading compound in the development of anticancer agents. (C) 2016 AACR.