title: Linear TMC-95-based proteasome inhibitors.
abstract: We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A. These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A. Structural variations in the amino acid side chains and termini greatly influenced both the efficiency and selectivity of action on a given type of active site. Inhibition constants were submicromolar (Ki approximately 300 nM) despite the absence of the entropically favorable constrained conformation that is characteristic of TMC-95A and its cyclic analogues. These linear compounds were readily prepared and reasonably stable in culture medium and could be optimized to inhibit one, two, or all three proteasome catalytic sites. Cytotoxicity assays performed on a series of human tumor cell lines identified the most potent inhibitors in cells.
authors.affiliation: Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, FRE 2852, CNRS, Université de Paris VI, Institut Jacques Monod, T43, 2 Place Jussieu, F 75251 Paris Cedex 05, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Basse
authors.forename: Sandrine
authors.initials: S
authors.lastname: Piguel
authors.forename: David
authors.initials: D
authors.lastname: Papapostolou
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ferrier-Berthelot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Richy
authors.forename: Maurice
authors.initials: M
authors.lastname: Pagano
authors.forename: Pierre
authors.initials: P
authors.lastname: Sarthou
authors.forename: Joëlle
authors.initials: J
authors.lastname: Sobczak-Thépot
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
authors.forename: Joëlle
authors.initials: J
authors.lastname: Vidal
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D061988:Proteasome Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; C408291:TMC-95A