2. Academic Validation
  3. Discovery of New Azaindole Metallo-Deubiquitinase CSN5 Inhibitors

Discovery of New Azaindole Metallo-Deubiquitinase CSN5 Inhibitors

  • J Med Chem. 2025 Mar 27;68(6):6748-6765. doi: 10.1021/acs.jmedchem.5c00184.
Pengcheng Lei 1,  Yu-Hang Yan 2,  Yingying Jiang 1,  Yanjun Wang 1,  Rui Xiong 1,  Jianlin Deng 1,  Hang Zhang 1,  Zhiwen Yang 1,  Weifeng Zhang 1,  Jing-Wei Wu 2,  Wenyi Liu 1,  Hui Lei 1,  Guo-Bo Li 2,  Lingling Yang 1
Affiliations

Affiliations

  • 1 College of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China.
  • 2 Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
PMID: 40053484 DOI: 10.1021/acs.jmedchem.5c00184
Abstract

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.

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