Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing new proteins. Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a polyubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein.
MLN2238 is a selective, potent, and reversible proteasome inhibitor, which inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM).
Epoxomicin(BU-4061T) is a potent anti-tumor agent isolated from Actinomycetes that is used as a selective and irreversible inhibitor of the 20S proteasome.
MLN2238 rapidly hydrolyzes to MLN2238, which is a selective, orally bioavailable, second-generation proteasome inhibitor, inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with an IC50 value of 3.4 nM (Ki of 0.93 nM), and also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites with IC50 of 31 and 3500 nM, respectively.
MG-101 is a potent inhibitor of cysteine proteases including calpain I (Ki = 190 nM), calpain II (Ki = 220 nM), cathepsin B (Ki = 150 nM), and cathepsin L (Ki = 500 pM).
Delanzomib(CEP-18770) is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity.
VR23 is a small molecule that potently inhibited the activities of trypsin-like proteasomes (IC50 = 1 nM), chymotrypsin-like proteasomes (IC50 = 50-100 nM), and caspase-like proteasomes (IC50 = 3 μM).
