Linear TMC-95-based proteasome inhibitors.
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.
Basse
Nicolas
N
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.
Piguel
Sandrine
S
Papapostolou
David
D
Ferrier-Berthelot
Alexandra
A
Richy
Nicolas
N
Pagano
Maurice
M
Sarthou
Pierre
P
Sobczak-Thépot
Joëlle
J
Reboud-Ravaux
Michèle
M
Vidal
Joëlle
J
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
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; C408291:TMC-95A