Discovery of New Azaindole Metallo-Deubiquitinase CSN5 Inhibitors
CSN5 is responsible for the deneddylation of cullin-RING E3 ubiquitin ligases and is closely linked to the development of various cancers. We previously developed a noncatalytic activity assay platform using novel fluorescent probes derived from azaindole inhibitors, which also highlighted the potential for further structural optimization of azaindoles. Herein, we report a series of new 4-NH-substituted azaindole derivatives, some of which showed nanomolar activity against the CSN5 subunit. Cellular assays revealed that the new azaindoles increase the cullin 1 neddylation in cancer cells. Importantly, they exhibit synergistic anticancer effects in combination with poly(ADP-ribose) polymerase inhibitors through increasing DNA damage. This work presents a new lead compound and a potential combination strategy for drug discovery targeting CSN5.
Authors
- Ruisheng Xiong (ORCID: https://orcid.org/0000-0002-8165-5863)
- Guo‐Bo Li (ORCID: https://orcid.org/0000-0002-4915-6677)
- Lingling Yang (ORCID: https://orcid.org/0000-0001-8397-8079)
- Jingwei Wu (ORCID: https://orcid.org/0000-0002-0285-3619)
- Yingying Jiang (ORCID: https://orcid.org/0000-0002-0788-8546)
- Hui Lei (ORCID: https://orcid.org/0000-0002-4757-586X)
- Pengcheng Lei (ORCID: https://orcid.org/0000-0002-9940-1765)
- Yu‐Hang Yan
- Weifeng Zhang (ORCID: https://orcid.org/0000-0003-1328-747X)
- Wenyi Liu (ORCID: https://orcid.org/0009-0003-4521-3624)
- Yanjun Wang (ORCID: https://orcid.org/0000-0003-3702-5693)
- Zhiwen Yang (ORCID: https://orcid.org/0000-0002-5712-9695)
- Hang Zhang (ORCID: https://orcid.org/0009-0006-2637-4694)
- Jianlin Deng (ORCID: https://orcid.org/0009-0006-1277-040X)
Institutions
- Xihua University (CN)
- Ministry of Education of the People's Republic of China (CN)
- Sichuan University (CN)
- Bioengineering Center (RU)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-07
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00184
- Citations
- 2
- Primary Topic
- Research on Leishmaniasis Studies
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- National Natural Science Foundation of China
- Department of Science and Technology of Sichuan Province
- Sichuan University
- National Key Research and Development Program of China