1. Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction.
- Author
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Wang, Xuefei, Du, Zeqian, Guo, Yuegui, Zhong, Jie, Song, Kun, Wang, Junyuan, Yu, Jianqiang, Yang, Xiuyan, Liu, Chen-Ying, Shi, Ting, and Zhang, Jian
- Subjects
COMPUTER-assisted molecular design ,STACKING interactions ,COLORECTAL cancer ,BOUND states ,CANCER-related mortality ,KINASE inhibitors - Abstract
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 π‒π stacking interactions were essential for inhibitor stabilization in the bound state. Furthermore, in vitro and in vivo 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. This study elucidated an ONIOM model-driven design and optimization of inhibitors targeting APC‒Asef based on the unique "Sandwich" π‒π interactions. [Display omitted] [ABSTRACT FROM AUTHOR]
- Published
- 2024
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