Benzothiophene-2-carboxamide derivatives as SENPs inhibitors with selectivity within SENPs family

The SUMO (small ubiquitin-related modifier)-specific proteases (SENPs) are responsible for the cleavage of SUMO from its target proteins, thus play important roles in the dynamic SUMOylation and deSUMOylation processes. SENPs are related to a variety of human diseases including cancer and represent a new class of potential therapeutic targets with mechanism of action that is likely to be different from that of current clinically used drugs. However, potent inhibitors that are selective within the SENPs family members still remain a challenge due to their high homology. In order to demonstrate the feasibility of developing selective inhibitors within the SENPs family, we chose SENP1/2/5 as representatives, aiming to identify inhibitors with selectivity among the members. Starting from a hit compound ZCL951 from virtual screening, a series of benzothiophene-2-carboxamide inhibitors were designed based on the protein structures of SENP1, 2, and 5. First, an unoccupied hydrophobic pocket was first identified which led to IC₅₀ as low as 0.56 μM. Furthermore, the ethylacetate 77 gave both submicromolar inhibitory activity and 33-fold selectivity for SENP2 versus SENP5. They are the most potent and selective nonpeptidic inhibitor reported so far for the SENPs family, as far as we are aware. Their structure-activity relationship was also discussed.