The proteasome is a multicatalytic proteolytic enzyme that is essential for the degradation of intracellular proteins thereby regulating processes such as signal-transduction, cell-cycle control, antigen processing and apoptosis. Inhibition of the proteasome offers a promising approach in the treatment of cancer. The majority of the inhibitors that have been developed react with the catalytic threonine residue within the active site. The natural product TMC-95, however, is a macrocyclic peptide that reversibly inhibits the proteasome through a hydrogen-bonding network between the enzyme subsites and the extended peptide backbone of the macrocycle. This research investigates the design and synthetic strategy of novel macrocyclic peptidyl inhibitors that simultaneously contain a reactive functional group. The design not only addresses inhibition through a hydrogen bonding array, as observed with TMC-95, but also aims to covalently modify the active site nucleophilic threonine residue.

Structure-based design and synthesis of bimodal proteasome inhibitors as therapeutic agents

243rd National Meeting (2012)

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