Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration
Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration
复制标题
APC-Asef 相互作用的肽模拟抑制剂可阻止结直肠癌迁移。
DOI：
10.1038/nchembio.2442
复制
发表时间：
2017-09-01
影响因子：
14.8
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Jiang, Haiming;Deng, Rong;Zhang, Jian
结肠腺瘤性息肉病(APC)与其受体ASEF的结合解除了ASEF的分子内负调控，导致结直肠癌细胞的异常迁移。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结直肠癌治疗的一个有吸引力的靶点。我们理性地设计了一系列模拟多肽的药物，作为APC界面的有效抑制剂。晶体结构、生化和细胞分析表明，APC囊袋中的肽类化合物通过破坏APC-ASEF相互作用来抑制结直肠细胞的迁移。通过使用模拟肽抑制剂作为化学探针，我们发现CDC42是参与APC刺激的结直肠癌细胞ASEF激活的下游GTP酶。我们的工作证明了利用APC-ASEF相互作用来调节结直肠癌细胞迁移的可行性，并提供了我们所知的第一类蛋白质-蛋白质相互作用抑制剂，可用于开发针对APC-ASEF信号的癌症治疗药物。
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.