Q-MOL LLC, San Diego, California, United States of America.
John Wayne Cancer Institute and Pacific Neuroscience Institute at Providence Saint John's Health Center, Santa Monica, CA, USA.
Sci Rep. 2020 May 15;10(1):8096. doi: 10.1038/s41598-020-60784-y.
Abnormal regulation of β-catenin initiates an oncogenic program that serves as a main driver of many cancers. Albeit challenging, β-catenin is an attractive drug target due to its role in maintenance of cancer stem cells and potential to eliminate cancer relapse. We have identified C2, a novel β-catenin inhibitor, which is a small molecule that binds to a novel allosteric site on the surface of β-catenin. C2 selectively inhibits β-catenin, lowers its cellular load and significantly reduces viability of β-catenin-driven cancer cells. Through direct binding to β-catenin, C2 renders the target inactive that eventually activates proteasome system for its removal. Here we report a novel pharmacologic approach for selective inhibition of β-catenin via targeting a cryptic allosteric modulation site. Our findings may provide a new perspective for therapeutic targeting of β-catenin.
β-连环蛋白的异常调节会引发致癌程序，成为许多癌症的主要驱动因素。尽管具有挑战性，但由于β-连环蛋白在维持癌症干细胞中的作用以及消除癌症复发的潜力，β-连环蛋白是一个有吸引力的药物靶点。我们已经确定了 C2，一种新型的β-连环蛋白抑制剂，它是一种小分子，可与β-连环蛋白表面的新型变构位点结合。C2 选择性地抑制β-连环蛋白，降低其细胞负荷，并显著降低β-连环蛋白驱动的癌细胞的活力。通过直接与β-连环蛋白结合，C2 使靶标失活，最终激活蛋白酶体系统以去除靶标。在这里，我们报告了一种通过靶向隐蔽变构调节位点选择性抑制β-连环蛋白的新型药理方法。我们的发现可能为β-连环蛋白的治疗靶向提供新的视角。
