https://orcid.org/0009-0002-3776-8788
Abstract
Background:
IκB kinase β (IKKβ) plays a pivotal role in the NF-κB signaling pathway and is considered a promising therapeutic target for various diseases.
Materials & methods:
The authors developed and validated a 3D pharmacophore model of IKKβ inhibitors via the HypoGen algorithm in Discovery Studio 2019, then performed virtual screening, molecular docking and kinase assays to identify hit compounds from the ChemDiv database. The compound with the highest inhibitory activity was further evaluated in adjuvant-induced arthritis rat models.
Results:
Among the four hit compounds, Hit 4 had the highest IKKβ inhibitory activity (IC50 = 30.4 ± 3.8), and it could significantly ameliorate joint inflammation and damage in vivo.
Conclusion:
The identified compound, Hit 4, can be optimized as a therapeutic agent for inflammatory diseases.
Plain language summary
This research paper focuses on the development and validation of IκB kinase β (IKKβ) inhibitors. IKKβ is a crucial enzyme that plays an important role in the NF-κB signaling pathway, which is involved in many diseases such as inflammatory diseases and cancers. The researchers used computer-aided drug design strategies to identify potential IKKβ inhibitors. First, they used a model to screen a large database of chemical compounds. Then, they conducted further tests to pinpoint the ones that could effectively inhibit IKKβ. Out of all the tested compounds, one referred to as ‘Hit 4’ showed the highest inhibitory activity. It was even able to significantly reduce joint inflammation and damage in rat models. Although many drugs targeting IKKβ have been developed, none are commercially available yet due to issues with efficacy or safety. Therefore, the findings of this study are significant and could lead to the development of new effective therapeutic agents for inflammatory diseases.
Graphical abstract
Supplementary data
To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.4155/fmc-2023-0261
Author contributions
L Li: data collection, manuscript preparation, kinase assays, animal experiments, data analysis; S Gong: research conception, manuscript revision. Authors contributed to the article and approved the submitted version.
Acknowledgments
The authors would like to acknowledge scholars’ contribution to the ChemDiv for the availability of the data. The authors are grateful to the editors and reviewers for their helpful comments on this paper. Meanwhile, the authors acknowledge the efforts of all researchers in developing Discovery Studio as well as ChemDraw software. Financial support via Xi’an Science and Technology Plan and the Key Research and Development Project of Shaanxi Province is acknowledged.
Financial disclosure
This work was supported by the National Natural Science Foundation of China (grant no. 81903268), the Shaanxi Province Key R&D Program (grant no. S2023-YF-YBSF-0261), Wu Jieping Medical Fund and the Shaanxi Province Key R&D Program (grant no. 2022SF-110). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.
Writing disclosure
No writing assistance was utilized in the production of this manuscript.
Ethical conduct of research
All animal experiments were carried out following the principles outlined in the Declaration of Helsinki and approved by the Institutional Animal Care and Use Committee of Xi’an Jiaotong University.
Data sharing statement
The results, data and figures in this manuscript have not been published elsewhere, nor are they under consideration by another publisher. Data will be made available on request.