Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system
(UPS) is one of the primary intracellular protein degradation systems, which is responsible for the
degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for
cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain
the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation. Encouraged
by success of bortezomib in the treatment of multiple myeloma, several second-generation
proteasome inhibitors have been developed based on natural resources, and are being tested in various
clinical settings. In this paper, we reviewed the most widely investigated proteasome inhibitors, including
their natural product origins, compound-discovery and optimization, as well as their current status in
both preclinical and clinical studies.
Keywords: Natural compound, ubiquitin proteasome system, proteasome inhibitor, drug discovery, cancer, clinical trial.
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