The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC–Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC–Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein–protein interaction inhibitors available for the development of cancer therapeutics targeting APC–Asef signaling.

中文翻译：

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APC-Asef相互作用的拟肽抑制剂可阻断结直肠癌的迁移

腺瘤性息肉病大肠杆菌（APC）与其受体Asef的结合减轻了Asef的分子内负调节作用，并导致人结肠直肠癌中异常的细胞迁移。由于其在转移扩散中的关键作用，APC和Asef之间的相互作用是抗大肠癌治疗的一个有吸引力的目标。我们合理地设计了一系列拟肽，它们可作为APC界面的有效抑制剂。晶体结构以及生化和细胞分析表明，APC口袋中的拟肽通过破坏APC-Asef相互作用来抑制结肠直肠细胞的迁移。通过使用拟肽抑制剂作为化学探针，我们发现CDC42是大肠癌细胞中参与APC刺激的Asef激活的下游GTPase。