Identification and Optimization of Novel Cathepsin C Inhibitors Derived from EGFR Inhibitors.
Weijie HouHuan SunYongfen MaChunyan LiuZhiyuan ZhangPublished in: Journal of medicinal chemistry (2019)
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.
Keyphrases
- epidermal growth factor receptor
- tyrosine kinase
- bone marrow
- advanced non small cell lung cancer
- structure activity relationship
- single cell
- small cell lung cancer
- small molecule
- mesenchymal stem cells
- oxidative stress
- high throughput
- amino acid
- protein protein
- cell therapy
- combination therapy
- drug discovery
- case control
- replacement therapy