Department of Pharmaceutical Sciences , University of Maryland School of Pharmacy , Baltimore , Maryland 21201 , United States.
National Center for Advancing Translational Sciences , National Institutes of Health , 9800 Medical Center Drive , Bethesda , Maryland 20892 , United States.
J Med Chem. 2019 Dec 26;62(24):11151-11164. doi: 10.1021/acs.jmedchem.9b01252. Epub 2019 Dec 10.
Dysregulation of the Wnt/β-catenin signaling pathway has been widely recognized as a pathogenic mechanism for colorectal cancer (CRC). Although numerous Wnt inhibitors have been developed, they commonly suffer from toxicity and unintended effects. Moreover, concerns have been raised in targeting this pathway because of its critical roles in maintaining stem cells and regenerating tissues and organs. On the basis of the anthelmintic drug pyrvinium and previous lead FX1128, we have developed a compound YW2065 () which demonstrated excellent anti-CRC effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of β-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity. The anti-CRC effect of YW2065 was highlighted by its promising efficacy in a mice xenograft model.
Wnt/β-连环蛋白信号通路的失调已被广泛认为是结直肠癌（CRC）的发病机制。尽管已经开发出许多 Wnt 抑制剂，但它们通常存在毒性和意外作用的问题。此外，由于该途径在维持干细胞和组织器官再生方面的关键作用，靶向该途径的安全性也受到了关注。基于驱虫药吡喹酮和先前的先导化合物 FX1128，我们开发了一种化合物 YW2065（），它在体外和体内均显示出优异的抗 CRC 效果。YW2065 通过稳定调节β-连环蛋白蛋白酶体降解的支架蛋白 Axin-1 来实现其对 Wnt 信号的抑制活性。同时，YW2065 还导致肿瘤抑制因子 AMPK 的激活，提供了另一种抗癌机制。此外，YW2065 表现出良好的药代动力学特性，没有明显的毒性。YW2065 在小鼠异种移植模型中的显著疗效突出了其抗 CRC 作用。
