Background: The 26S proteasome is a proteolytic complex of multimeric protease, which operates at
the executive end of the Ubiquitin-Proteasome System (UPS) and degrades the polyubiquitylated proteins.
Methods: After a brief introduction of 26S proteasome and Ubiquitin-Proteasome System (UPS), this review
focuses on the structure and function of the 26S proteasome in intracellular protein level regulation. Then,
physiological regulation mechanisms and processes are elaborated. In addition, the advantages and defects of
approved 26S proteasome inhibitors were discussed. Finally, we summarized the novel peptide 26S proteasome
inhibitors according to their structural classifications, highlighting their design strategies, inhibitory activity and
Structure-Activity Relationships (SARs).
Results: Cellular function maintenance relies on the proteasome metabolizing intracellular proteins to control
intracellular protein levels, which is especially important for cancer cells to survive and proliferate. In primary
tumors, proteasomes had a higher level and more potent activity. Currently, the approved small peptide inhibitors
have proved their specific 26S proteasome inhibitory effects and considerable antitumor activities, but with
obvious defects. Increasingly, novel peptide inhibitors are emerging and possess promising values in cancer
Conclusion: Overall, the 26S proteasome is an efficient therapeutic target and novel 26S proteasome inhibitors
hold potency for cancer therapy.