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.