Structure-Based Design of Inhibitors Selective for Human Proteasome β2c or β2i Subunits.

ABSTRACT: Subunit-selective proteasome inhibitors are valuable tools to assess the biological and medicinal relevance of individual proteasome active sites. Whereas the inhibitors for the β1c, β1i, β5c, and β5i subunits exploit the differences in the substrate-binding channels identified by X-ray crystallography, compounds selectively targeting β2c or β2i could not yet be rationally designed because of the high structural similarity of these two subunits. Here, we report the development, chemical synthesis, and biological screening of a compound library that led to the identification of the β2c- and β2i-selective compounds LU-002c (4; IC₅₀ β2c: 8 nM, IC₅₀ β2i/β2c: 40-fold) and LU-002i (5; IC₅₀ β2i: 220 nM, IC₅₀ β2c/β2i: 45-fold), respectively. Co-crystal s

SUBMITTER: Xin BT 

PROVIDER: S-EPMC6378654 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature