Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors

In
the course of developing the biochemistry to chemistry activity-based
protein profiling (BTC-ABPP) method, we herein unexpectedly discovered
that the epidermal growth factor receptor irreversible inhibitor WZ4002
also functioned as a low micromolar inhibitor of cathepsin C (CatC),
a promising target for the treatment of numerous inflammatory and
autoimmune diseases. Building on from this discovery, and following
structure–activity relationship investigations guided by computational
modeling, a novel series of pyridine scaffold compounds were developed
as irreversible CatC inhibitors, further culminated in identifying
a highly potent and selective inhibitor 22, which displays
good metabolic stability and oral bioavailability. In vivo studies
revealed that compound 22 clearly displays the ability
to inhibit CatC, consequently leading to efficient inhibition of downstream
neutrophil serine proteases in both bone marrow and blood. The overall
excellent profile of compound 22 made it an interesting
candidate for further preclinical investigation.