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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

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

Villoutreix Bruno O BO Khatib Abdel-Majid AM Cheng Yan Y Miteva Maria A MA Maréchal Xavier X Vidal Joëlle J Reboud-Ravaux Michèle M

Oncotarget 20170201 6

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 β2 trypsin-like catalytic site with a preference for the immunoproteasome β2i over the constitutive proteasome β2c, while some act on the β5 site and post-acid site β ...[more]

PMID: 28060729

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Project description:The goal of this study was to determine if subunit displacement and/or alterations in proteasome biosynthesis could explain the changes observed in the levels of constitutive proteasomes (c-20S) and immunoproteasomes (i-20S) in the spinal cords of mice with experimental autoimmune encephalomyelitis (EAE). To this end, EAE was induced in C57BL/6 mice by immunization with MOG35-55 peptide. Spinal cords were collected at different times during the disease course and used for western blotting, RNA analysis, and immunohistochemistry. The results show that, as expression of i-20S and the activator PA28 rise in EAE, there is a concomitant decline in that of c-20S at the mRNA and protein level. These changes are observed in neurons and astrocytes but not in oligodendrocytes. The increased amounts of the i-20S-specific subunit β5i and PA28α/β in EAE correlate with the levels of interferon-γ and its downstream effectors p-signal transducer and activator of transcription 1 and interferon regulatory factor-1, but not with those of nuclear factor kappa-light-chain-enhancer of activated B cells. This suggests that the signal transducer and activator of transcription 1/interferon regulatory factor-1 pathway is solely responsible for the induction of these subunits. The decrease in the mRNA and protein levels corresponding to the c-20S-specific subunit β5 may also be due to reduced expression of the nuclear factor (erythroid-derived 2)-like-1 (Nrf1 or Nfe2l1), specifically Nrf1α and Nrf1β. Low Nfe2l1 mRNA expression is unlikely caused by reduced mammalian target of rapamycin signaling but could be the result of diminished pre-B-cell leukemia homeobox-1 transcription factor levels. Together, these findings suggest that a combination of subunit displacement and reduced Nrf1 expression may be responsible for c-20S impairment in EAE. The present work provides insights into the dynamics of proteasome expression in the CNS of EAE mice and is the first to explore Nrf1 signaling in an inflammatory demyelinating disorder.

Dataset Information

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

Publications

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

Similar Datasets

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