New Peptidomimetic Boronates for Selective Inhibition of the Chymotrypsin-like Activity of the 26S Proteasome

作者：Zhang Xiaozhou; Adwal Alaknanda^*; Turner Andrew G; Callen David F; Abell Andrew D

来源：ACS Medicinal Chemistry Letters, 2016, 7(12): 1039-1043.

DOI：10.1021/acsmedchemlett.6b00217

• 26S proteasome inhibitors
• boronic ester
• solid cancer
• chymotrypsin-like activity
• immunoproteasome

Proteasome is a large proteinase complex that degrades proteins via its three catalytic activities. Among these activities, the "chymotrypsin-like" activity has emerged as the focus of drug discovery in cancer therapy. Here, we report new peptidomimetic boronates that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new specific proteasome inhibitors were demonstrated to have higher in vitro potency and selective cytotoxicity for cancer cells compared to benchmark proteasome inhibitors: bortezomib and carfilzomib. In breast cancer cell lines, treatment with la or 2a induced accumulation of the high molecular weight polyubiqutinated proteins at similar levels observed for bortezomib and carfilzomib, indicating that cancer cell death caused by la/2a is chiefly due to proteasome inhibition.

• 出版日期2016-12