Abstract
Cathepsin S, a lysosomal cysteine protease, is primarily secreted from immune system and plays a major role in antigen presentation through degradation of invariant chain that is associated with the major histocompatibility class II complex (MHC II). Thus, cathepsin S is related to autoimmune diseases such as rheumatoid arthritis and psoriasis. Recently, scientists also found that cathepsin S is highly expressed in malignant cancer cells and plays an important role in cancer cells invasion, migration, and metastasis. Interruption of its activity by inhibitors has been extensively evaluated as a new therapeutic approach for cancer treatment. On the basis of cathepsin S proteolytic mechanism, 16 peptidic α-ketoamide inhibitors were designed and synthesized for specifically targeting cathepsin S and suppressing its functions in tumor progression. Results revealed that 13 compounds with Ki values lower than 10 nM and 5 of them even provide picomolar range inhibition activity. Among them, compound 27c was selected for further animal experiment and the results showed obvious inhibition of tumor cell progression and increase of the survival rate. To further improve oral bioavailability and long circulation half-life of the synthesized compound in medicinal application, compound 65 with quaternary ammonium group and peptidomometics compounds 86 and 89 with 1,2,3-triazole group were successfully synthesized. All of these compounds remain nanomolar scale inhibition activity. We are studying their pharmacokinetics and exploring their potentials as anticancer drugs.