Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide. At initial diagnosis, approximately 20% of patients are diagnosed with metastatic CRC (mCRC). Although the APC‒Asef interaction is a well-established target for mCRC therapy, the discovery and development of effective and safe drugs for mCRC patients remains an urgent and challenging endeavor. In this study, we identified a novel structural scaffold based on MAI inhibitors, the first-in-class APC‒Asef inhibitors we reported previously. ONIOM model-driven optimizations of the N-terminal cap and experimental evaluations of inhibitory activity were performed, and 24-fold greater potency was obtained with the best inhibitor compared to the parental compound. In addition, the cocrystal structure validated that the two-layer stacking interactions were essential for inhibitor stabilization in the bound state. Furthermore, and studies have demonstrated that novel inhibitors suppressed lung metastasis in CRC by disrupting the APC‒Asef interaction. These results provide an intrinsic structural basis to further explore drug-like molecules for APC‒Asef-mediated CRC therapy.

中文翻译：

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破坏 APC-Asef 相互作用的有效抑制剂的计算机辅助分子设计和优化

结直肠癌（CRC）是全球癌症死亡的第二大原因。初次诊断时，大约 20% 的患者被诊断患有转移性 CRC (mCRC)。尽管 APC-Asef 相互作用是 mCRC 治疗的既定目标，但为 mCRC 患者发现和开发有效且安全的药物仍然是一项紧迫且具有挑战性的工作。在这项研究中，我们确定了一种基于 MAI 抑制剂的新型结构支架，这是我们之前报道的一流的 APC-Asef 抑制剂。进行了 ONIOM 模型驱动的 N 末端帽优化和抑制活性的实验评估，与母体化合物相比，最佳抑制剂的效力提高了 24 倍。此外，共晶结构验证了两层堆积相互作用对于抑制剂在结合状态下的稳定至关重要。此外，研究表明新型抑制剂通过破坏 APC-Asef 相互作用来抑制 CRC 肺转移。这些结果为进一步探索 APC-Asef 介导的 CRC 治疗药物样分子提供了内在的结构基础。