Discovery ofNew Azaindole Metallo-DeubiquitinaseCSN5 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.