Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction
Xuefei Wang1,2, Zeqian Du3, Yuegui Guo4
1Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
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.
Insights
Researchers developed novel inhibitors targeting the APC-Asef interaction to combat metastatic colorectal cancer (CRC). These potent compounds demonstrated efficacy in suppressing lung metastasis, offering a promising therapeutic avenue for CRC patients.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Colorectal cancer (CRC) is a leading cause of cancer mortality globally, with approximately 20% of patients diagnosed with metastatic disease (mCRC).
- The interaction between Adenomatous Polyposis Coli (APC) and Activator of SREP Expression (Asef) is a validated therapeutic target for mCRC.
- Developing effective and safe drugs targeting this interaction remains a significant challenge.
Purpose of the Study:
- To identify and optimize novel inhibitors targeting the APC-Asef interaction for potential mCRC therapy.
- To investigate the structural basis for inhibitor efficacy and their mechanism of action.
- To evaluate the therapeutic potential of these novel inhibitors in preclinical models.
Main Methods:
- Utilized a novel structural scaffold based on previously reported MAI inhibitors.
- Employed ONIOM (Our Own N-layered Integrated molecular Orbital and molecular Mechanics) model-driven optimizations.
- Conducted experimental evaluations of inhibitory activity, cocrystal structure analysis, and in vitro/in vivo studies.
Main Results:
- Achieved a 24-fold increase in potency with optimized inhibitors compared to the parental compound.
- Validated the importance of two-layer π–π stacking interactions for inhibitor stabilization via cocrystal structure.
- Demonstrated suppression of lung metastasis in CRC models by disrupting the APC-Asef interaction.
Conclusions:
- Novel MAI-based inhibitors exhibit significantly enhanced potency and efficacy against APC-Asef-mediated CRC.
- The structural insights provide a foundation for developing drug-like molecules for CRC therapy.
- These findings offer a promising strategy for targeting metastatic colorectal cancer by disrupting the APC-Asef interaction.
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