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

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

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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.

APC-AsefPeptidomimeticComputer-aided molecular designONIOM modelπ-π stackingMetastatic colorectal cancer

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

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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

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

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

Department of Colorectal and Anal Surgery,Xinhua Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

Basic Science Research Center Base(Pharmaceutical Science),Yantai University,Yantai 264005,China

Medicinal Chemistry and Bioinformatics Center,Shanghai Jiao Tong University,School of Medicine,Sh

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National Key R&D Program of ChinaKey Research and Construction Programs of Ningxia Hui Autonomous Region,ChinaStarry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study,ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of Chinaopen fund of state key laboratory of Pharmaceutical Biotechnology,Nanjing University,Chinaopen fund of Basic Science Research Center Base,China

2023YFF12051032022BEG01002SN-ZJU-SIAS-0072223700581925034KF-202201Pharmaceutical Science Y202203

2024

10.1016/j.apsb.2024.03.020

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(6)
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