Evaluation of new cathepsin K inhibitors (585.4)

Abstract

Cathepsin K is a lysosomal cysteine protease that is predominantly expressed in osteoclasts. It has also been found in elevated levels in people with rheumatoid arthritis, prostate cancer, and breast cancer. Due to its strong collagenase activity, cathepsin K has been described as a major enzyme responsible for the turnover of extracellular matrix proteins and plays a fundamental role in bone resorption. Cathepsin K is a novel drug target for osteoporosis, osteoarthritis, and bone metastasis. Here, we report screening and evaluation of five new synthetic inhibitors against recombinant cathepsin K. The recombinant human procathepsin K was overexpressed in E. coli, purified from inclusion bodies, and activated by pepsin treatment. Cathepsin K inhibition assay was performed spectrophotometrically with N‐Carbobenzoxy‐L‐Phenylalanyl‐Arginine‐4‐nitroanilide hydrochloride as the chromogenic substrate. Data analysis of the effectiveness of these inhibitors will be used to foster future development of newer effective inhibitors for the treatment osteoporosis and possibly rheumatoid arthritis and cancer.Grant Funding Source: National Cancer Institute at NIH (Grant No. 3R15CA086933‐04 and 3R15CA086933‐04A2S1) and WIU