Proteases, enzymes responsible for protein hydrolysis, play important roles in a variety of cellular signaling pathways. The proteasome, an important protease that is a crucial component of the ubiquitin-proteasome pathway (UPP), is responsible for the quality-control of newly synthesized proteins in eukaryotic cells. Many UPP substrates are involved in the regulation of apoptosis and the cell cycle. Defects in the UPP are believed to play a role in a number of disease states, including cancer. Hence, the proteasome has been validated as an important target for the treatment of cancers, particularly multiple myeloma. While numerous examples of proteasome inhibitors have been reported, there remains a demand for potent therapeutics with higher specificity for the target proteasome. We present here the synthesis and kinetic inhibition study of the first examples of aza-peptide proteasome inhibitors, incorporating an aza-P1 amino acid residue and an α-aldehyde or α-ketone moiety as the active site electrophilic warhead. This new class of reversible inhibitors demonstrates competitive inhibition for the 20S proteasome with measured K<sub>i</sub> values in the µM range. These novel inhibitors show potential for the development of a new class of protease inhibitors of the aza-peptide variety.

Aza-peptide aldehydes and ketones: A new class of proteasome inhibitors

253rd National Meeting (2017)

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