Small-molecule inhibitor: TMC-95

Name

History: TMC-95A and its diastereomers, TMC-95B to D, were isolated from the fermentation broth of Apiospora montagnei Sacc. TC 1093 by Koguchi et al. (2000).
Peptidases inhibited: TMC-95A inhibited the activities of catalytic unit 1 (peptidylglutamyl-peptide hydrolyzing), catalytic unit 2 (trypsin-like) and catalytic unit 3 (chymotrypsin-like) of the 20S proteasome with IC50 values of 60 nM, 200 nM, and 5.4 nM, respectively. The TMC-95B isomer inhibited similarly, whereas the inhibitory activities of TMC-95C and D were 20 to 150 times weaker. TMC-95A did not inhibit m-calpain, cathepsin L or trypsin at 30 microM, suggesting that it is high selectivity for the proteasomal activities (Koguchi et al., 2000).
Mechanism: Inhibition is reversible. The structures of complexes between TMC-95A and yeast 20S proteasome, and the mode of binding of the inhibitor, have been described by Groll et al. (2001) and Kaiser et al. (2004).
Pharmaceutical relevance: There is strong evidence that such inhibitors of the proteasome as bortezomib have therapeutic potential, so other inhibitors of the proteasomal peptidase activities are also of great interest.

CID at PubChem: 5287563
Structure
Formula weight: 683
Related inhibitors: In the four forms of TMC-95, identities of R₁, R₂, R₃ and R₄ are H, OH, CH₃, H (TMC-95A), H, OH, H, CH₃ (TMC-95B), OH, H, CH₃, H (TMC-95C) and OH, H, H, CH₃, respectively (Groll et al., 2001).