Optimization of a series of dipeptides with a P3 β-neopentyl asparagine residue as non-covalent inhibitors of the chymotrypsin-like activity of human 20S proteasome

• DOI: 10.1039/c2md20060k
• Publication Date: 2012-04-19T14:25:45Z
• Authors: Christopher Black...; Cynthia Barrett; Jonathan L. Blank; Frank J. Bruzzese; Nancy Bump; Lawrence R. Dick; Paul Fleming; Khristofer Garcia; Paul Hales; Matthew Jones; Jane X. Liu; Masayuki Nagayoshi; Darshan S. Sappal; Michael D. Sintchak; Christopher Tsu; Cindy Xia; Xiansi Zhou; Kenneth M. Gigstad
• Keywords: Residue (chemistry)

Inhibition of the proteasome by covalent inhibitors is a clinically proven anti-cancer therapy. We report here that dipeptides with P3 neopentyl Asn residue are potent, reversible, non-covalent selective for chymotryptic activity 20S in vitro and cells. The X-ray structure compound 20 complex yeast reveals importance hydrophobic bonding interactions group within S3 binding pocket β5 sub-unit. Four compounds show comparable potencies to boronic acid panel assays.