Li Yonghe, Oliver Patsy G, Lu Wenyan, Pathak Vibha, Sridharan Sivaram, Augelli-Szafran Corinne E, Buchsbaum Donald J, Suto Mark J
Drug Discovery Division, Southern Research, 2000 Ninth Avenue South, Birmingham, AL 35255, USA.
Department of Radiation Oncology, The University of Alabama at Birmingham, Birmingham, AL, USA.
Cancer Lett. 2017 Mar 28;389:41-48. doi: 10.1016/j.canlet.2016.12.030. Epub 2016 Dec 30.
Activation of Wnt/β-catenin signaling is associated with pancreatic and colorectal cancer, among others. To-date, there are no FDA-approved small molecule Wnt/β-catenin inhibitors and many past efforts resulted in compounds with undesirable off-target effects. We recently identified a series of benzimidazole analogs as potent inhibitors of Wnt/β-catenin signaling. Here, we show that the lead compound SRI36160 displayed selective Wnt inhibition and potent antiproliferative activity in pancreatic and colorectal cancer cells. Moreover, SRI36160 had no effect on STAT3 and mTORC1 signaling in pancreatic and colorectal cancer cells, and was not effective in inhibiting proliferation of non-cancerous cells. Our findings suggest that this series of benzimidazole analogs presents a novel approach for the treatment of Wnt-dependent cancers such as colorectal and pancreatic cancer.
Wnt/β-连环蛋白信号通路的激活与胰腺癌和结直肠癌等多种癌症相关。迄今为止，尚无美国食品药品监督管理局（FDA）批准的小分子Wnt/β-连环蛋白抑制剂，过去的许多研究成果得到的化合物都具有不良的脱靶效应。我们最近鉴定出一系列苯并咪唑类似物，它们是Wnt/β-连环蛋白信号通路的强效抑制剂。在此，我们表明先导化合物SRI36160在胰腺癌细胞和结肠直肠癌细胞中表现出选择性Wnt抑制作用和强大的抗增殖活性。此外，SRI36160对胰腺癌细胞和结肠直肠癌细胞中的STAT3和mTORC1信号通路没有影响，并且在抑制非癌细胞增殖方面无效。我们的研究结果表明，这一系列苯并咪唑类似物为治疗诸如结直肠癌和胰腺癌等Wnt依赖性癌症提供了一种新方法。
