Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors.
Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors.
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DOI：
10.1021/acs.jmedchem.8b01888
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发表时间：
2019-03
影响因子：
7.3
通讯作者：
F. Shirai;T. Tsumura;Yoko Yashiroda;Hitomi Yuki;H. Niwa;Shin Sato;Tsubasa Chikada;Y. Koda;K. W
中科院分区：
文献类型：
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作者：
F. Shirai;T. Tsumura;Yoko Yashiroda;Hitomi Yuki;H. Niwa;Shin Sato;Tsubasa Chikada;Y. Koda;K. W
经典WNT通路在癌症发病机制中起重要作用。据报道，端锚聚合酶（TNKS/TNKS 2）的聚（ADP-核糖）聚合酶催化活性的抑制通过阻止AXIN（Wnt/β-连环蛋白信号传导的负调节物）的聚ADP-核糖基化依赖性降解来降低Wnt/β-连环蛋白信号。为了研究端锚聚合酶和Wnt通路抑制对肿瘤生长的影响，我们着手寻找具有合适药物样性质的TNKS/TNKS 2小分子抑制剂。从1a开始，高通量筛选命中，发现螺吲哚啉衍生物40 c（RK-287107）是一种有效的TNKS/TNKS 2抑制剂，对PARP 1酶具有>7000倍的选择性，可抑制WNT响应性TCF报告基因活性和人结肠直肠癌细胞系科洛-320 DM的增殖。RK-287107在小鼠异种移植模型中也表现出剂量依赖性肿瘤生长抑制作用。这些观察结果表明，RK-287107是开发新型端锚聚合酶抑制剂作为抗癌剂的有前景的先导化合物。
The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/β-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/β-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as anticancer agents.