Design, Synthesis, and Evaluation of Aza-Peptide Michael Acceptors as Human 20S Proteasome Inhibitors: Extension to the Prime Site.

ABSTRACT: Current FDA-approved proteasome inhibitor (PI) drugs, such as bortezomib, carfilzomib, and ixazomib, have significantly improved the treatment of multiple myeloma (MM) over the past 20 years. However, due to their associated severe side effects and multidrug resistance developed by many MM patients, treatment typically falters within a year. Although other mechanisms within the ubiquitin-proteasome-dependent protein degradation machinery are targeted to overcome this drug resistance, inhibition of the proteasome itself remains an attractive target. To this end, we report aza-peptide Michael acceptors as a new class of PIs. Peptidyl analogues, such as bortezomib, carfilzomib, and ixazomib, employ chemical warheads at their C-termini, and therefore the peptide backbone engages with the nonpr

SUBMITTER: Border SE 

PROVIDER: S-EPMC12311731 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature