Peptidomimetic boronates as proteasome inhibitors

Michelle-Zhang_1_sq13 September 2016:

CNBP researchers Xiaozhou (Michelle) Zhang & Prof Andrew Abell explore peptidomimetic boronates as proteasome inhibitors in the latest issue of ACS Medicinal Chemistry Letters.

Journal: ACS Medicinal Chemistry Letters.

Title: New Peptidomimetic Boronates for Selective Inhibition of the Chymotrypsin-Like Activity of the 26S Proteasome.

Authors: Xiaozhou Zhang, Alaknanda Adwal, Andrew G Turner, David F Callen and Andrew D Abell.

Abstract: 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 demonstrated 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 1a or
2a induced accumulation of the high molecular weight polyubiqutinated proteins at similar levels observed for borte-zomib and carfilzomib, indicating that cancer cell death caused by 1a/2a is chiefly due to proteasome inhibition.

The paper can be accessed online.