Computer-aided molecular design and optimization of potent inhibitors disrupting APC-Asef interaction  

作　　者：Xuefei Wang Zeqian Du Yuegui Guo Jie Zhong Kun Song Junyuan Wang Jianqiang Yu Xiuyan Yang Chen-Ying Liu Ting Shi Jian Zhang 

机构地区：[1]Department of Pathophysiology,Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education,Shanghai Jiao Tong University,School of Medicine,Shanghai 200025,China [2]Key Laboratory of Protection,Development and Utilization of Medicinal Resources in Liupanshan Area,Ministry of Education,Peptide&Protein Drug Research Center,School of Pharmacy,Ningxia Medical University,Yinchuan 750004,China [3]State Key Laboratory of Microbial Metabolism,Joint International Research Laboratory of Metabolic and Developmental Sciences,School of Life Sciences and Biotechnology,Shanghai Jiao Tong University,Shanghai 200240,China [4]Department of Colorectal and Anal Surgery,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [5]Basic Science Research Center Base(Pharmaceutical Science),Yantai University,Yantai 264005,China [6]Medicinal Chemistry and Bioinformatics Center,Shanghai Jiao Tong University,School of Medicine,Shanghai 200025,China [7]State Key Laboratory of Pharmaceutical Biotechnology,Nanjing University,Nanjing 210023,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第6期2631-2645,共15页药学学报（英文版）

基　　金：funded by the National Key R&D Program of China(2023YFF1205103 to Jian Zhang);the Key Research and Construction Programs of Ningxia Hui Autonomous Region(2022BEG01002 to Jian Zhang,China);the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study(SN-ZJU-SIAS-007 to Jian Zhang,China);the National Natural Science Foundation of China(22237005 and 81925034 to Jian Zhang);the open fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University(KF-202201 to Jian Zhang,China);the open fund of Basic Science Research Center Base(Pharmaceutical Science Y202203 to Xiuyan Yang,China).

摘　　要：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-layerπ-πstacking 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.

关 键 词：APC-Asef PEPTIDOMIMETIC Computer-aided molecular design ONIOM model π-πstacking Metastatic colorectal cancer 

分 类 号：R914[医药卫生—药物化学]