Proteasome

Marizomib (ML858) is a novel irreversible brain-permeable proteasome inhibitor that inhibits CT-L (β5), CT-T-laspase-like (C-L, β1), and trypsin-like (T-L, β2) 20S proteasomes with IC50s of 3.5, 28, and 430 nM, respectively.

Bortezomib (LDP 341) is a 20S proteasome inhibitor (Ki=0.6 nM) that is reversible and selective. Bortezomib has antitumor activity and inhibits NF-κB, which can disrupt the cell cycle and induce apoptosis.

MG-132 (Z-Leu-Leu-Leu-al) is a 26S proteasome inhibitor (IC50=100 nM) that is cell-permeable and reversible. MG-132 acts as an autophagy activator and also induces apoptosis.

Omarigliptin (MK-3102) has been used in trials studying the treatment of Type 2 Diabetes Mellitus and Chronic Renal Insufficiency.

Vildagliptin (LAF237) is a cyanopyrrolidine-based, orally bioavailable inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. Vildagliptin's cyano moiety undergoes hydrolysis and this inactive metabolite is excreted mainly via the urine.

TCH-165 is a small molecule modulator of proteasome assembly, resulting in an increase in 20S levels. The increase in the level of free 20S corresponds to enhanced proteolysis of IDPs.

Sitagliptin (MK0431), a new oral hypoglycemic (anti-diabetic drug), is a new dipeptidyl peptidase-4 (DPP-4) inhibitor. This enzyme-inhibiting drug is used either alone or in combination with metformin or thiazolidinedione for treatment of type 2 diabetes mellitus. The drug can competitively inhibit a protein/enzyme and DPP-4, that leads to an incremental amount of active incretins (GLP-1 and GIP), the diminished amount of release of glucagon and increased release of insulin.

UK-101 is a potent and selective inhibitor of the immunoproteasome LMP2, inhibiting β1i (LMP2), β1c (LMP2), and β5 (LMP2), with IC50s of 104 nM, 15 μM, and 1 μM. UK-101 has a 144-fold and 10-fold higher affinity for β1i than for the distribution of β1c and β5 subunits. UK-101 induces apoptosis and can be used to study prostate cancer related diseases.

LXE408 fumarate is an orally active, non-competitive and kinetoplastid-selective proteasome inhibitor. LXE408 fumarate has an IC50 of 0.04 μM for L. donovani proteasome and an EC50 of 0.04 μM for L. donovani. LXE408 fumarate has a low propensity to cross the blood brain barrier. LXE408 fumarate has the potential for visceral leishmaniasis (VL) research.

Bortezomib-pinanediol is a proteasome inhibitor. is a prodrug of Bortezomib.

Proteasome inhibitor IX (PS-IX) is an inhibitor of chymotrypsin-like activity of the 20S proteasome (IC50 ~1 μM). Proteasome inhibitor IX shows potent anticancer activity. Proteasome inhibitor IX exhibits HCT116 p53+ + cells growth inhibitory activity(IC50 = 1.49 μM).

1G244 is an inhibitor of DPP8 9 with antiatherosclerotic and antimyeloma properties. 1G244 had the IC50 values of 14 and 53 nM against DPP8 and DPP9, and The Ki values for 1G244 were 0.9 and 4.2 nM for DPP8 and DPP9

LMP7-IN-1 may used in the research of inflammatory and autoimmune diseases, neurodegenerative diseases, proliferative diseases and cancer, is an inhibitor of immunoproteasome (LMP7).

Cilastatin (MK0791) is a renal dehydropeptidase-I and leukotriene D4 dipeptidase inhibitor. Since the antibiotic, IMIPENEM, is hydrolyzed by dehydropeptidase-I, which resides in the brush border of the renal tubule, cilastatin is administered with imipenem to increase its effectiveness. The drug also inhibits the metabolism of leukotriene D4 to leukotriene E4.

MLN2238 suppresses the chymotrypsin-like proteolytic (β5) site of the 20S proteasome(Ki50=0.93 nM, IC50=3.4 nM/). The biologically active form of MLN9708 (Ixazomib Citrate) is MLN2238 in aqueous solutions or plasma.

Oprozomib (PR-047) (ONX 0912) , an inhibitor for CT-L activity of 20S proteasome β5(IC50=36 nM)/LMP7(IC50=82 nM), is orally bioavailable. Oprozomib also has potential antineoplastic activity.

Calpeptin is a potent, cell-permeable calpain inhibitor.

Talabostat mesylate (PT100) is an orally active, selective inhibitor of dipeptidyl peptidases IV (DPP4, IC50: 0.18 nM), including tumor-associated fibroblast activation protein. This agent may also stimulate the production of colony stimulating factors, such as granulocyte colony-stimulating factor (G-CSF), resulting in the stimulation of hematopoiesis.

18α-Glycyrrhetinic acid (Enoxolone) is an inhibitor of NF-kB and an activator of the proteasome, and functions as a longevity-promoting and anti-aggregation factor in multicellular organisms. It induces apoptosis.

Delanzomib (CEP-18770) is an orally active inhibitor of the chymotrypsin-like activity of proteasome (IC50: 3.8 nM). It only marginally inhibits the tryptic and peptidylglutamyl activities of the proteosome.

Tripterin (Celastrol) is a natural product, a proteasome inhibitor that inhibits the pancreatic rennet-like activity of the 20S proteasome (IC50=2.5 μM). Tripterin has anti-inflammatory, anti-infectious, and immunomodulatory properties.

PI-1840（IC50 = 27 nM）is a reversible and selective chymotrypsin-like (CT-L) inhibitor, with little proteasome proteolytic effects on trypsin-like (T-L) and postglutamyl-peptide-hydrolysis-like (PGPH-L).

Pepstatin (Pepsin Inhibitor S 735A) is a specific aspartic proteases inhibitor produced by actinomycetes, and inhibits the aspartic proteases cathepsin D, pepsin and renin.

Aprotinin (Traskolan) a broad-spectrum serine protease inhibitor, inhibiting the activity of a number of different esterases and proteases, including trypsin, chymotrypsin, kallikrein, plasmin, tissue plasminogen activator, and tissue and leukocytic proteinases.

ML604440 is a cell permeable proteasome β1i (LMP2) subunit inhibitor.

Carfilzomib (PR-171) is a proteasome inhibitor that irreversibly binds to the chymotrypsin of the 20S proteasome. Carfilzomib has antitumor activity and may be used to treat multiple myeloma.

ONX-0914 (PR-957) is an effective and specific immunoproteasome inhibitor, which has minimal cross-reactivity for the constitutive proteasome.

Ixazomib (MLN2238) , a second generation, boron-containing peptide proteasome inhibitor (PI), inhibits the chymotrypsin-like proteolytic (β5) site of the 20S proteasome (IC50/Ki: 3.4/0.93 nM, in cell-free assays), also inhibits the caspase-like (β1) and trypsin-like (β2) proteolytic sites (IC50: 31/3500 nM).

Proteasome β2c/i-IN-1 (compound 37) serves as a selective inhibitor targeting the β2c and β2i subunits of the human proteasome [1].

Aclacinomycin A (Aclarubicin) hydrochloride is a fluorescent molecule and the first described non-peptidic inhibitor showing discrete specificity for the CTRL (chymotrypsin-like) activity of the 20S proteasome. Aclacinomycin A hydrochloride is also a dual inhibitor of topoisomerase I and II.

Proteasome-IN-5, also known as compound 5, acts as a proteasome inhibitor [1].

PR 39 (porcine) acetate is a noncompetitive, reversible and allosteric proteasome inhibitor. PR 39 (porcine) acetate reversibly binds to the α7 subunit of the proteasome and blocks degradation of NF-κB inhibitor IκBα by the ubiquitin-proteasome pathway.

β5i-IN-1 is a selective inhibitor of β5i, exhibiting potent activity with an IC50 of 8.463 nM. It modulates immune responses by promoting the release of TNF-α and IL-6 and affecting NF-κB transcriptional activity. This compound has applications in the research of idiopathic pulmonary fibrosis [1].

Lactacystin is an antibiotic Streptomyces spp. the metabolite and is an effective and selective proteasome inhibitor (IC50: 4.8 μM for 20S proteasome). Lactacystin inhibits cell growth and induces neurite outgrowth and also inhibits the lysosomal enzyme cathepsin A.

Z-Gly-Pro-Phe-Leu-CHO (Z-GPFL-CHO) is a tetrapeptide aldehyde serving as a selective and potent proteasome inhibitor, demonstrating inhibition constants (Ki) of 1.5 µM, 2.3 µM, and 40.5 µM for branched-chain amino acid-preferred, small neutral amino acid-preferred, and chymotrypsin-like activities, respectively, and an inhibitory concentration (IC50) of 3.1 µM for peptidyl-glutamyl peptide hydrolyzing activity [1].

LU-002i is a selective inhibitor targeting the human proteasome subunits β2c and β2i, demonstrating an inhibitory concentration (IC50) of 220 nM for β2i [1].

Gabexate mesylate (FOY) is a serine proteinase inhibitor used therapeutically in the treatment of pancreatitis, disseminated intravascular coagulation (DIC), and as a regional anticoagulant for hemodialysis. The drug inhibits the hydrolytic effects of thrombin, plasmin, and kallikrein, but not of chymotrypsin and aprotinin.

RAMB4 (PTP1B-IN-9) is a ubiquitin-proteasome system (UPS)-stressor,with anticancer activity.

MUN57694 is an inhibitor of 26S proteasome.

Z-LLY-FMK (Calpain Inhibitor IV) serves as an inhibitor of calpain, a family of proteases implicated in the apoptosis of various cell systems. Specifically, this compound suppresses intestinal cell apoptosis following common bile duct ligation [1].

Trelagliptin succinate (SYR-472 succinate) is a long-acting inhibitor of dipeptidyl peptidase-4 (DPP-4), being developed for the treatment of type 2 diabetes (T2D).

RA375, an inhibitor of RPN13 (26S proteasome regulatory subunit), enhances UPR signaling, ROS production, and apoptosis. Demonstrating ten times the efficacy against cancer lines compared to RA190, RA375 owes its increased activity to nitro ring substituents and the inclusion of a chloroacetamide warhead.

Z-Leu-Leu-Tyr-COCHO is a potent inhibitor of chymotrypsin-like activity, exhibiting a Ki value of 3.0 nM [1].

Z-Ala-Arg-Arg-AMC (Fluorogenic Proteasome Substrate) serves as a fluorogenic substrate designed to assay the trypsin-like activity within the proteasome [1].

AC-55541 (AOB2796) is a novel PAR2 agonist; activated PAR2 signaling in cellular proliferation assays, phosphatidylinositol hydrolysis assays, and Ca(2+) mobilization assays, with potencies ranging from 200 to 1000 nM.

Brensocatib (AZD7986) is a Dipeptidyl peptidase 1 (DPP1) inhibitor (pIC50s: 6.85, 7.7, 7.6, 7.8, and 7.8 in human, rat, mouse, rabbit, and dog, respectively).

DD1 (HUN85111) is a proteasome inhibitor that induces human myeloid tumor-selective apoptosis.

PSI is a proteasome inhibitor.

Nateglinide (Senaglinide) is an oral hypoglycemic agent and amino acid derivative that stimulates insulin secretion from the pancreas and is used in the therapy of type 2 diabetes. Nateglinide has been linked to rare instances of clinically apparent acute liver injury.

Saxagliptin hydrate (Onglyza hydrate) is a selective and reversible DPP4 inhibitor (IC50: 26 nM; Ki: 1.3 nM).