Novel organic proteasome inhibitors identified by virtual and in vitro screening.
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.
Basse
Nicolas
N
Enzymologie Moleculaire et Fonctionnelle, UR4, UPMC-Universite de Paris 6, Case 256, 7 Quai Saint Bernard, F 75252 Paris Cedex 05, France.
Montes
Matthieu
M
Maréchal
Xavier
X
Qin
Lixian
L
Bouvier-Durand
Michelle
M
Genin
Emilie
E
Vidal
Joëlle
J
Villoutreix
Bruno O
BO
Reboud-Ravaux
Michèle
M
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
D000970:Antineoplastic Agents; D010879:Piperazines; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013450:Sulfones; D000077489:Piperazine