title: Novel organic proteasome inhibitors identified by virtual and in vitro screening.
abstract: Proteasome inhibition is a promising strategy for treating cancers. Herein, we report the discovery of novel drug-like inhibitors of mammalian proteasome 20S using a multistep structure-based virtual ligand screening strategy. Sulfone- or piperazine-containing hits essentially belong to the under-represented class of noncovalent and nonpeptidic proteasome inhibitors. Several of our compounds act in the micromolar range and are cytotoxic on human tumoral cell lines. Optimization of these molecules could lead to better anticancer therapy.
authors.affiliation: Enzymologie Moleculaire et Fonctionnelle, UR4, UPMC-Universite de Paris 6, Case 256, 7 Quai Saint Bernard, F 75252 Paris Cedex 05, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Basse
authors.forename: Matthieu
authors.initials: M
authors.lastname: Montes
authors.forename: Xavier
authors.initials: X
authors.lastname: Maréchal
authors.forename: Lixian
authors.initials: L
authors.lastname: Qin
authors.forename: Michelle
authors.initials: M
authors.lastname: Bouvier-Durand
authors.forename: Emilie
authors.initials: E
authors.lastname: Genin
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vidal
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D061988:Proteasome Inhibitors; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013450:Sulfones; D000077489:Piperazine