RIKEN Program for Drug Discovery and Medical Technology Platforms , 2-1 Hirosawa , Wako , Saitama 351-0198 , Japan.
Division of Molecular Biotherapy, Cancer Chemotherapy Center , Japanese Foundation for Cancer Research , 3-8-31 Ariake , Koto-ku, Tokyo 135-8850 , Japan.
J Med Chem. 2019 Apr 11;62(7):3407-3427. doi: 10.1021/acs.jmedchem.8b01888. Epub 2019 Apr 1.
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.
经典 WNT 通路在癌症发病机制中发挥着重要作用。据报道，通过抑制端锚聚合酶（Tankyrases）的聚 ADP-核糖聚合酶催化活性，可以防止 AXIN 的多聚 ADP-核糖化依赖性降解，从而减少 Wnt/β-catenin 信号。AXIN 是 Wnt/β-catenin 信号的负调控因子。为了研究 Tankyrase 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特性的 Tankyrase/TNKS2 小分子抑制剂。以高内涵筛选的 hit1a 为起点，我们发现了螺吲哚啉衍生物 40c（RK-287107），它是一种有效的 Tankyrase/TNKS2 抑制剂，对 PARP1 酶具有 >7000 倍的选择性，能够抑制 WNT 反应性 TCF 报告基因活性和人结直肠癌细胞系 COLO-320DM 的增殖。RK-287107 在小鼠异种移植模型中也表现出剂量依赖性的肿瘤生长抑制作用。这些观察结果表明，RK-287107 是一种很有前途的新型 Tankyrase 抑制剂先导化合物，可作为抗癌药物。
