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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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Structure-Based Optimization of TBK1 Inhibitors.

Wenxuan Sun^1,2, Yuting Xie², Qiancheng Xia^1,2

¹Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing 100084, China.

ACS Medicinal Chemistry Letters

|April 16, 2025

Summary

Researchers designed potent TBK1 inhibitors using structure-based drug design. A novel inhibitor was discovered, showing enhanced immune response without self-toxicity, offering a new therapeutic avenue for TBK1-related diseases.

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Area of Science:

Biochemistry
Immunology
Medicinal Chemistry

Background:

TBK1 (TANK-binding kinase 1) is a key regulator of immunity, inflammation, and autophagy.
Dysregulation of TBK1 is implicated in various diseases, highlighting its potential as a therapeutic target.

Purpose of the Study:

To design and identify potent and selective inhibitors of TBK1 using a structure-based lead optimization approach.
To develop novel therapeutic strategies for TBK1-associated diseases.

Main Methods:

Construction and virtual screening of a focused library of over 5,000 compounds against the TBK1 binding site.
Molecular dynamics simulations and MM/PBSA binding free energy calculations to refine compound selection.
Chemical synthesis and biological evaluation of selected TBK1 inhibitor candidates.

Main Results:

Identification of a highly potent TBK1 inhibitor with an IC50 of 775 pM, representing a significant improvement from the initial hit (19.57 μM).
The novel inhibitor scaffold demonstrated excellent enzymatic inhibition and enhanced immune-mediated cytotoxicity.
The developed inhibitor showed no significant cytotoxicity when used as a single agent.

Conclusions:

Structure-based drug design is effective for discovering potent and selective TBK1 inhibitors.
The novel TBK1 inhibitor is a promising candidate for developing targeted therapies for diseases associated with TBK1 dysregulation.
This study provides a strong foundation for further preclinical development of TBK1-targeted therapeutics.