L-4, a Well-Tolerated and Orally Active Inhibitor of Hedgehog Pathway, Exhibited Potent Anti-tumor Effects Against Medulloblastoma in vitro and in vivo
L-4, a Well-Tolerated and Orally Active Inhibitor of Hedgehog Pathway, Exhibited Potent Anti-tumor Effects Against Medulloblastoma in vitro and in vivo
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DOI：
10.3389/fphar.2019.00089
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发表时间：
2019-02
影响因子：
5.6
通讯作者：
Mingfei Zhu;Hong Wang;Chenglin Wang;Yan-fen Fang;T. Zhu;Weili Zhao;Xiaochun Dong;Xiongwen Zhang
中科院分区：
文献类型：
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作者：
Mingfei Zhu;Hong Wang;Chenglin Wang;Yan-fen Fang;T. Zhu;Weili Zhao;Xiaochun Dong;Xiongwen Zhang
抑制异常Hedgehog（Hh）通路已被证明是一种很有前途的治疗手段，可用于治疗基底细胞癌（BCC）、髓母细胞瘤（MB）等肿瘤，目前已有两种药物（Vismodegib、Sonidegib）被批准用于治疗BCC，更多的抑制剂正在临床研究中。但Hh抑制剂的不良反应和耐药性限制了其应用。本研究通过双荧光素酶报告基因分析筛选了61个含酞嗪或二甲基哒嗪中心骨架的合成化合物作为新的Hh信号抑制剂的候选物。在这些化合物中，L-4在Shh-Light II测定中显示出2.33 nM的IC 50值。L-4对Hh通路有明显的抑制作用，并通过拮抗Smo受体阻断Hh通路。值得注意的是，L-4可以显著抑制由Smo突变体（D473 H）引起的Hh途径活性，Smo突变体（D473 H）对现有药物如维莫德吉显示出强抗性特性。在Ptch+/-; p53-/- MB同种异体移植物模型中，口服给予的L-4在体内表现出显著的剂量依赖性抗肿瘤功效。此外，L-4在ICR小鼠急性毒性试验中表现出良好的耐受性。这些证据表明L-4是一种有效的、耐受性良好的口服Hedgehog通路抑制剂，有望成为Hh靶向抗癌药物的候选药物。
Inhibition of aberrant Hedgehog (Hh) pathway had been proved to be a promising therapeutic intervention in cancers like basal cell carcinoma (BCC), medulloblastoma (MB), and so on. Two drugs (Vismodegib, Sonidegib) were approved to treat BCC and more inhibitors are in clinical investigation. However, the adverse effects and drug resistance restricted the use of Hh inhibitors. In the present study, 61 synthesized compounds containing central backbone of phthalazine or dimethylpyridazine were screened as candidates of new Hh signaling inhibitors by performing dual luciferase reporter assay. Among the compounds, L-4 exhibited an IC50 value of 2.33 nM in the Shh-Light II assay. L-4 strongly inhibited the Hh pathway in vitro and blocked the Hh pathway by antagonizing the smoothened receptor (Smo). Remarkably, L-4 could significantly suppress the Hh pathway activity provoked by Smo mutant (D473H) which showed strong resistant properties to existing drugs such as Vismodegib. Orally administered L-4 exhibited prominent dose-dependent anti-tumor efficacy in vivo in Ptch+/-; p53-/- MB allograft model. Furthermore, L-4 showed good tolerance in acute toxicity test using ICR mice. These evidences indicated that L-4 was a potent, well-tolerated, orally active inhibitor of Hedgehog pathway, and might be a promising candidate in development of Hh-targeted anti-cancer drugs.