title: Blockade of the malignant phenotype by β-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 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 β1 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.
authors.affiliation: INSERM, U 973, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.affiliation: INSERM, LAMC, U 1029, Pessac, France.
authors.forename: Abdel-Majid
authors.initials: AM
authors.lastname: Khatib
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6, UMR 8256, ERL U1164, B2A, IBPS, Paris, France.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: INSERM, U 973, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Miteva
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6, UMR 8256, ERL U1164, B2A, IBPS, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Maréchal
authors.affiliation: Institut des Sciences Chimiques de Rennes, Université de Rennes 1, UMR-CNRS 6226, Rennes, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vidal
authors.affiliation: Sorbonne Universités, UPMC Université Paris 6, UMR 8256, ERL U1164, B2A, IBPS, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D003198:Computer Simulation; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D021122:Protein Subunits; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D046988:Proteasome Endopeptidase Complex
keywords: immunoproteasome; noncovalent inhibitors; piperazine; proteasomes; virtual screening