title: New Peptidomimetic Boronates for Selective Inhibition of the Chymotrypsin-like Activity of the 26S Proteasome.
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 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 with1aor2ainduced accumulation of the high molecular weight polyubiqutinated proteins at similar levels observed for bortezomib and carfilzomib, indicating that cancer cell death caused by1a/2ais chiefly due to proteasome inhibition.
authors.affiliation: Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia; Centre for Personalised Cancer Medicine, Discipline of Medicine, The University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia.
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Zhang
authors.affiliation: ARC Centre of Excellence for Nanoscale BioPhotonics, Institute of Photonics and Advanced Sensing, Department of Chemistry, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Alaknanda
authors.initials: A
authors.lastname: Adwal
authors.affiliation: ARC Centre of Excellence for Nanoscale BioPhotonics, Institute of Photonics and Advanced Sensing, Department of Chemistry, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Turner
authors.affiliation: ARC Centre of Excellence for Nanoscale BioPhotonics, Institute of Photonics and Advanced Sensing, Department of Chemistry, The University of Adelaide , Adelaide, South Australia 5005, Australia.
authors.forename: David F
authors.initials: DF
authors.lastname: Callen
authors.affiliation: Department of Chemistry, The University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia; Centre for Personalised Cancer Medicine, Discipline of Medicine, The University of Adelaide, North Terrace, Adelaide, South Australia 5005, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Abell
keywords: 26S proteasome inhibitors; boronic ester; chymotrypsin-like activity; immunoproteasome; solid cancer