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.
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A potent, selective, cell-permeable Calpain inhibitor with Ki of 0.26 uM for m-calpain; displays 20-fold selectivity over m-calpain; attenuates the SLLVY-AMC hydrolysis induced by maitotoxin in SY5Y cells; decreases cytotoxicity induced by oxidized low-density lipoprotein (oxLDL) in HMEC-1 cells.
A potent and selective calpain inhibitor with Ki of 0.21 uM/0.37 uM for u-calpain/m-calpain, respectively; shows no inhibition for other proteases (cathepin B, papain, trypsin and thermolysin (Ki> 500 uM); attenuate shypoxic/hypoglycemic injury to cerebrocortical neurons in culture and excitotoxic injury to Purkinje cells in cerebellar slices.
RA190 (RA-190) is a reversible, highly selective, orally active inhibitor of the proteasomal ubiquitin receptor Rpn13, exhibits potent anti-proliferative effects against MM lines (IC50<0.1 uM) and HPV-transformed cells (IC50<0.3 uM); inhibits proteasome function, triggering rapid accumulation of polyubiquitinated proteins; profoundly reduced growth of MM and ovarian cancer xenografts.
FV-162 is a potent, orally bioavailable, irreversible proteasome inhibitor with potent antimyeloma activity (IC50<60 nM); induces rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibits tumor growth in myeloma xenograft model.
KZR-616 (KZR616) is a potent, selective dual immunoproteasome subunit LMP7/LMP2 inhibitor with IC50 of 39 nM/139 nM, weakly inhibits β5, MECL-1 and no acitivty against β1 subunit; shows no inhibition at 10 uM against a broad selectivity panel of 20 serine, metallo-, cysteine and aspartyl proteases and 11 hydrolases; demonstrates efficacy in the anti-collagen antibody induced arthritis (CAIA) models.
A potent, selective, orally bioavailable proteasome inhibitor with IC50 of 3.4 nM; binds to and inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome with Ki of 0.93 nM, weakly inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites (IC50 of 31 and 3,500 n M); inhibits growth and induces apoptosis in MM cells; shows improved antitumor activity in models of lymphoma compared with bortezomib.
PI-1840 is a potent, selective, noncovalent, reversible inhibitor for proteasome chymotrypsin-like (CT-L) activity with IC50 of 27 nM, shows no effect on trypsin-like and peptidylglutamyl peptide hydrolyzing activities (IC50>100 uM); also displays 100-fold more selectivity for the constitutive proteasome over the immunoproteasome; induces the accumulation of proteasome substrates p27, Bax, and IκB-α, inhibits survival pathways and viability, and induces apoptosis in intact cancer cells, also sensitizes human cancer cells to the mdm2/p53 disruptor Nutlin; suppresses the growth in nude mice of human breast tumor xenografts.
A potent inhibitor of trypsin-like proteasome (IC50=1 nM), chymotrypsin-like proteasome (IC50=50-100 nM) and caspase-like proteasome (IC50=3 uM); targets the β2 of the 20S proteasome catalytic subunit and structurally distinct from other known proteasome inhibitors and selectively kills cancer cells by apoptosis, with little effect on noncancerous cells.
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); activates p53-dependent apoptosis in tumor cell lines; increases activated p53, p21 and caspase levels and promotes cell cycle arrest through inhibition of cyclin D degradation in vitro.
Delanzomib is a potent, orally active proteasome inhibitor with IC50 of 3.8 nM against chymotrypsin-like proteasome activity; demonstrates marginal inhibition of the tryptic and peptidyl glutamyl activities of the proteosome; down-modulates the NF-kappaB activity and the expression of several NF-kappaB downstream effectors, induces apoptotic cell death in MM cells; demonstrates tumor regression in MM xenografts with favorable tumor selectivity profile.
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