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Small-Molecule Inhibitors of the Proteasome's Regulatory Particle.


ABSTRACT: Cells need to synthesize and degrade proteins consistently. Maintaining a balanced level of protein in the cell requires a carefully controlled system and significant energy. Degradation of unwanted or damaged proteins into smaller peptide units can be accomplished by the proteasome. The proteasome is composed of two main subunits. The first is the core particle (20S?CP), and within this core particle are three types of threonine proteases. The second is the regulatory complex (19S?RP), which has a myriad of activities including recognizing proteins marked for degradation and shuttling the protein into the 20S?CP to be degraded. Small-molecule inhibitors of the 20S?CP have been developed and are exceptional treatments for multiple myeloma (MM). 20S?CP inhibitors disrupt the protein balance, leading to cellular stress and eventually to cell death. Unfortunately, the 20S?CP inhibitors currently available have dose-limiting off-target effects and resistance can be acquired rapidly. Herein, we discuss small molecules that have been discovered to interact with the 19S?RP subunit or with a protein closely associated with 19S?RP activity. These molecules still elicit their toxicity by preventing the proteasome from degrading proteins, but do so through different mechanisms of action.

SUBMITTER: Muli CS 

PROVIDER: S-EPMC6765334 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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