Blockade of the malignant phenotype by ?-subunit selective noncovalent inhibition of immuno- and constitutive proteasomes.

ABSTRACT: A structure-based virtual screening of over 400,000 small molecules against the constitutive proteasome activity followed by in vitro assays led to the discovery of a family of proteasome inhibitors with a sulfonyl piperazine scaffold. Some members of this family of small non-peptidic inhibitors were found to act selectively on the ?2 trypsin-like catalytic site with a preference for the immunoproteasome ?2i over the constitutive proteasome ?2c, while some act on the ?5 site and post-acid site ?1 of both, the immunoproteasome and the constitutive proteasome. Anti-proliferative and anti-invasive effects on tumor cells were investigated and observed for two compounds. We report novel chemical inhibitors able to interfere with the three types of active centers of both, the immuno- and constitutive proteasomes. Identifying and analyzing a novel scaffold with decorations able to shift the binders' active site selectivity is essential to design a future generation of proteasome inhibitors able to distinguish the immunoproteasome from the constitutive proteasome.

SUBMITTER: Villoutreix BO 

PROVIDER: S-EPMC5354670 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature