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

Proteasome-activating peptide 1 enhances chymotrypsin-like proteasomal catalytic activity, boosting proteolytic rates both in vitro and within cultured cells. Additionally, it inhibits protein aggregation in a cellular model of amyotrophic lateral sclerosis [1].

Proteasome-activating peptide 1 TFA is a potent activator of the proteasome, enhancing chymotrypsin-like proteasomal catalytic activity and thereby increasing proteolytic rates both in vitro and in culture. Additionally, it inhibits protein aggregation in cellular models of amyotrophic lateral sclerosis (ALS) [1].

Proteasome-IN-1 is an inhibitor of proteasome.

MS6105 is a chimeric LDH protein hydrolysis-targeted PROTAC that degrades LDHA and LDHB efficiently, with its activity contingent on both time and the ubiquitin-proteasome system, exhibiting anticancer properties [1]. Additionally, as a click chemistry reagent possessing an Alkyne group, MS6105 can partake in copper-catalyzed azide-alkyne cycloaddition (CuAAc) reactions with Azide-bearing molecules.

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

Potent and selective BTK Degrader (IC50 = 5.1 nM); degrades BTK in a proteasome- and CRBN-dependent manner. Suppresses BTK signaling and proliferation in mantle cell lymphoma (MCL) cells by degrading BTK, IKFZ1, and IKFZ3 (3 validated targets in B-cell malignancies). Also degrades Ibrutinib (Cat. No. 6813) -resistant C481S-BTK mutant cancer cells. Exhibits no binding against a panel of 468 kinases at 1 μM. Reduces tumor burden and extends survival in lymphoma patient-derived xenograft models.

MS9449 is a potent PROTAC EGFR degrader, exhibiting dissociation constants (Kd) of 17 nM for EGFR WT and 10 nM for EGFR L858R. It effectively mediates the degradation of mutant EGFRs via both ubiquitin/proteasome system (UPS) and autophagy/lysosome pathways, and robustly suppresses the proliferation of NSCLC cells, indicating its potential utility in anticancer research [1].

VCP/p97 inhibitor-1, a highly effective compound, inhibits VCP/p97 (also known as Cdc48, CDC-48, or Ter94) with an IC 50 of 54.7 nM. This inhibitor induces a disruption in protein homeostasis and interferes with the degradation process of misfolded polypeptides by the ubiquitin-proteasome system (UPS).

SS47, a PROTAC -based HPK1 degrader , exerts proteasome-mediated HPK1 degradation. The degradation of HPK1 via SS47 also significantly enhances the?in?vivo?antitumor efficacy of BCMA CAR-T cell research. HPK1, an?immunosuppressive?regulatory kinase, is a promising target for cancer immunotherapies [1] .

Lmtk3-in-1 is a potent ATP-competitive lemur tyrosine kinase 3 (LMTK3) (Kd=2.5 μM) inhibitor that degrades LMTK3 through the ubiquitin proteasome pathway. LMTK3-IN-1 has shown anticancer activity in a variety of cancer cell lines and in vivo BC mouse models. LMTK3-IN-1 (10-20 μM) can induce the apoptosis of BC cell line.

(±)15-HETE is a alkyl chain-based linker for PROTACs which joins two essential ligands, crucial for forming PROTAC molecules. This linker enables selective protein degradation by leveraging the ubiquitin-proteasome system within cells.

WBC100 (14-D-Valine-TPL) is a potent, selective, and orally active c-Myc glue degrader that targets the ubiquitin E3 ligase CHIP-mediated 26S proteasome pathway, primarily utilized in research for c-Myc overexpressing tumors [1].

Pomalidomide-C5-Dovitinib (compound 2) is a PROTAC that links Pomalidomide and Dovitinib via a CRBN connector, exhibiting potent antiproliferative activity in FLT3-ITD+ acute myeloid leukemia (AML) cells. It promotes the ubiquitin-proteasome-dependent degradation of FLT3-ITD and KIT proteins, thereby effectively inhibiting their downstream signaling pathways and presenting research potential in FLT3-ITD+ AML [1].

MS9427 is a potent PROTAC EGFR degrader, demonstrating high affinity for EGFR with dissociation constants (K d s) of 7.1 nM for the wild-type (WT) EGFR and 4.3 nM for the L858R mutant EGFR, indicating selective degradation of the mutant over the WT EGFR. This degradation occurs through both ubiquitin/proteasome system (UPS) and autophagy/lysosome pathways. Furthermore, MS9427 effectively inhibits the proliferation of non-small cell lung cancer (NSCLC) cells, positioning it as a potential therapeutic agent in anticancer research [1].

Phthalimide-PEG3-C2-OTs (Compound 5) is a PROTAC linker composed of PEGs. It is utilized in the synthesis of various PROTACs, which involve the connection of two distinct ligands through a linker. One ligand is specific for an E3 ubiquitin ligase, while the other ligand is designed for targeting the specific protein of interest. Through leveraging the intracellular ubiquitin-proteasome system, PROTACs are capable of selectively degrading target proteins [1].

RN-18 antagonizes Vif function and inhibits HIV-1 replication only in the presence of A3G. RN-18 increases cellular A3G levels in a Vif-dependent manner and increases A3G incorporation into virions without inhibiting general proteasome-mediated protein degradation. RN-18 enhances Vif degradation only in the presence of A3G, reduces viral infectivity by increasing A3G incorporation into virions and enhances cytidine deamination of the viral genome.

CaMKIIα-PHOTAC is a photochemically targeted chimera (PHOTAC) that specifically targets Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα). This molecule facilitates the ubiquitination and subsequent proteasome-mediated degradation of CaMKIIα when exposed to certain light wavelengths. Under illumination, CaMKIIα-PHOTAC diminishes synaptic functions and weakens evoked field excitatory postsynaptic potentials in the mouse hippocampus, thus impacting physiological responses. Additionally, it is crucial for sustaining long-term potentiation and memory functions within dendritic domains [1].

PROTAC IDO1 Degrader-1, a pioneering compound, efficiently targets indoleamine 2,3-dioxygenase 1 (IDO1) for ubiquitination and degradation by recruiting IDO1 to the CRBN E3 ligase, thereby facilitating its entry into the ubiquitin-proteasome system (UPS) with a DC50 of 2.84 μM. This compound also moderately enhances the tumor-killing efficacy of HER2 CAR-T cells[1].

MS9427 TFA is a potent PROTAC-based EGFR degrader, exhibiting dissociation constants (Kd) of 7.1 nM for wild-type EGFR and 4.3 nM for the L858R EGFR mutation. It preferentially degrades the mutant EGFR, sparing the wild-type form, utilizing both the ubiquitin/proteasome system (UPS) and the autophagy/lysosome pathways. Its efficacy extends to the significant inhibition of non-small cell lung cancer (NSCLC) cell proliferation, indicating its potential utility in anticancer research [1].

Phthalimide-PEG4-PDM-OTBS is a PROTAC linker comprised of polyethylene glycols (PEGs). This compound is utilized in the synthesis of a range of PROTACs, which consists of two distinct ligands connected by a linker. One ligand binds to an E3 ubiquitin ligase, while the other ligand binds to the target protein. By leveraging the intracellular ubiquitin-proteasome system, PROTACs selectively degrade target proteins[1].

20S Proteasome activator 1 is a 20S proteasome activator with IC50 of 0.3 μM for trypsin-like sites, 0.7 μM for chymotrypsin-like sites and 1.8 μM for caspase sites. 20S Proteasome activator 1 prevents the accumulation of pathogenic alpha-synuclein A53T mutants through translation in the cellular system, thereby reducing the probability of disease occurrence. The 20S Proteasome activator 1 can be used to study neurodegenerative diseases.

PROTAC BCR-ABL Degrader-1 (compound PROTAC 1), featuring a 2-oxoethyl linker, promotes Bcr-Abl degradation through the ubiquitin-proteasome pathway and demonstrates antiproliferative effects on K562 cells, suggesting its utility in cancer research [1].

GSPT1 Degrader-1 (Compound 9q) effectively facilitates the degradation of G1 to S phase transition 1 (GSPT1) through the ubiquitin-proteasome system and induces G0/G1 phase arrest and apoptosis in cells [1].

Baceridin, a cyclic hexapeptide and proteasome inhibitor, can be isolated from the culture medium of Epiphytic Bacillus. It has the ability to impede cell cycle progression and induce apoptosis in tumor cells via a p53-independent pathway, making it a valuable agent in cancer research [1].

1. Steviol (NSC-226902), a natural sweetener, it inhibits proliferation of the gastrointestinal cancer cells intensively. 2. Steviol can induce a significant increase in CYP3A29 expression. 3. Steviol inhibits the proliferation of the human osteosarcoma U2OS cell line in a dose- and time-dependent manner. 4. Steviol can treat polycystic kidney disease, it slowed cyst growth, in part, by reducing AQP2 transcription, promoted proteasome, and lysosome-mediated AQP2 degradation.

Rpn11-IN-1 is an effective and selective inhibitor of proteasome subunit Rpn11 (IC50: 390 nM).

PROTAC TG2 Degrader-1 (Compound 11) is a VHL-based PROTAC that targets tissue transglutaminase (TG2) and exhibits a binding affinity with a K D of 68.9 μM. This compound effectively decreases TG2 levels in ovarian cancer cells through a proteasome-dependent pathway [1].

KZR-616, a first-in-class inhibitor of the immunoproteasome, selectively targets the LMP7 (IC50: 39/57 nM=hLMP7/mLMP7) and LMP2 (IC50: 131/179 nM=hLMP7/mLMP7) subunits of the immunoproteasome. KZR-616 has the potential for the research of multiple autoimmune diseases[1][2]. KZR-616 also inhibits MECL-1 subunit (IC50=623 nM) and constitutive proteasome β5 subunit (IC50=688 nM). KZR-616 maintains LMP7 and LMP2 selective inhibition in MOLT-4 cells. KZR-616 (250 nM) shows a comparable cytokine inhibition profile peripheral blood mononuclear cells (PBMC)[1].KZR-616 is an immunoproteasome-selective inhibitor identified based on the optimization of ONX-0914 and PR-924 [3]. KZR-616 (5 mg/kg; i.v.; dosing was repeated on days 6, 8, 11, and 13) shows efficacy in the anticollagen antibody induced arthritis (CAIA) model[1]. [1]. Johnson HWB, et al. Required Immunoproteasome Subunit Inhibition Profile for Anti-Inflammatory Efficacy and Clinical Candidate KZR-616 ((2 S,3 R)- N-(( S)-3-(Cyclopent-1-en-1-yl)-1-(( R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-(( S)-2-(2-morpholinoacetamido)propanamido)propenamide). J Med Chem. 2018 Dec 27;61(24):11127-11143. [2]. Muchamuel T, et al. FRI0296 Kzr-616, a selective inhibitor of the immunoproteasome, blocks the disease progression in multiple models of systemic lupus erythematosus (SLE). Annals of the Rheumatic Diseases 2018;77:685. [3]. Xi J, et al. Immunoproteasome-selective inhibitors: An overview of recent developments as potential drugs for hematologic malignancies and autoimmune diseases. Eur J Med Chem. 2019;182:111646.

TUS-007, a modified CANDDY (Chemical knockdown with Affinity aNd Degradation DYnamics) molecule originally derived from a proteasome inhibitor, scarcely affects proteasome activity. It is a potent, orally active degrader of KRAS G12D/V, effective in cell-free chemical knockdown of KRAS G12D/V. Furthermore, TUS-007 has been shown to suppress tumor growth [1].

USP28-IN-2 is a selective USP28 inhibitor (IC50 = 0.3 μM), demonstrating high specificity compared to USP2, USP7, USP8, USP9x, UCHL3, and UCHL5. This compound exhibits cytotoxic effects on cancer cells and induces the degradation of c-Myc via the ubiquitin-proteasome pathway. Additionally, USP28-IN-2 reduces ankyrin-1/2 levels in vitro and potentiates the responsiveness of colorectal cancer cells to Regorafenib [1].

Ac-Nle-Pro-Nle-Asp-AMC is a specific substrate for the 26S proteasome and is utilized in analyzing the proteasome's caspase-like activity [1] [2] [3].

Phthalimide-PEG4-MPDM-OH, a PROTAC linker with a PEGs composition, has applications in the synthesis of various PROTACs. These PROTACs consist of a linker connecting two distinct ligands: one binds to an E3 ubiquitin ligase, while the other binds to the target protein. By leveraging the intracellular ubiquitin-proteasome system, PROTACs selectively induce the degradation of target proteins [1].

BC-05, an orally active inhibitor targeting CD13 and the proteasome, displays potent inhibition with IC50 values of 0.13 μM against human CD13 and 1.39 μM for the 20S proteasome. It is utilized in the research of multiple myeloma [1].

Boc-C1-PEG3-C4-OH is an Alkyl/ether-based PROTAC linker utilized in the synthesis of PROTACs, which are characterized by their structure comprising two distinct ligands tethered by a linker. One ligand of PROTACs binds to an E3 ubiquitin ligase, while the other binds to the target protein. By leveraging the intracellular ubiquitin-proteasome system, PROTACs facilitate the targeted degradation of specific proteins[1].

C6 urea ceramide is an inhibitor of neutral ceramidase.1 It increases total ceramide levels in wild-type mouse embryonic fibroblasts (MEFs) and in HT-29 colon cancer cells but not in MEFs lacking neutral ceramidase. It inhibits proliferation of, and induces apoptosis and autophagy in HT-29, but not non-cancerous RIE-1, cells when used at concentrations of 5 and 10 μM. C6 urea ceramide decreases total β-catenin, increases phosphorylated β-catenin, and induces colocalization of β-catenin with the 20S proteasome in HT-29 and HCT116, but not RIE-1, cells. It reduces tumor growth and increases C16, C18, C20, and C24 ceramide levels in tumor tissue in an HT-29 mouse xenograft model when administered at doses of 1.25, 2.5, and 5 mg/kg for five days. |1. García-Barros, M., Coant, N., Kawamori, T., et al. Role of neutral ceramidase in colon cancer. FASEB J. 30(12), 4159-4171 (2016).

TP-110 is a new proteasome inhibitor, which shows potent growth inhibition in various tumor cell lines. Treatment with TP-110 for 24 h in vitro induced apoptosis in multiple myeloma cell line RPMI8226. TP-110 reduced the intrinsic inhibitor of apoptosis proteins (IAPs), cIAP-1 and XIAP, that suppress executioner caspases.

Enzyme-IN-1 (compound 1), a peptide-based inhibitor of N-terminal nucleophile (Ntn) hydrolases, specifically targets and inhibits the chymotrypsin-like activity (CT-L) of the 20S proteasome. This compound may possess potential anti-inflammatory properties [1].

PSI (TFA) is a potent proteasome inhibitor effective against the proliferation of primary effusion lymphoma (PEL) cells, utilized in the study of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection and related lymphomas [1].

20S Proteasome-IN-4 (Compound 7) is an orally active inhibitor of the 20S proteasome, selectively targeting the parasite form and demonstrating brain penetration capabilities. It exhibits a potent IC50 value of 6.3 nM against the T. b. brucei 20S proteasome, rendering it applicable for human African trypanosomiasis (HAT) research [1].

YW2065 has excellent anti-colorectal cancer effects in vitro and in vivo. YW2065 achieves its inhibitory activity for Wnt signaling by stabilizing Axin-1, a scaffolding protein that regulates proteasome degradation of β-catenin. Simultaneously, YW2065 also led to the activation of the tumor suppressor AMPK, providing an additional anticancer mechanism. In addition, YW2065 showed favorable pharmacokinetic properties without obvious toxicity.

AP-1, a miniaturized proteolysis-targeting chimera (PROTAC) incorporating an anaplastic lymphoma kinase (ALK) ligand connected to (±)-thalidomide via an ultrashort linker, effectively degrades ALK fusion proteins such as NPM-ALK in Karpas-299 cells and EML4-ALK and ALKF1174L in SN-N-SH and NCI H3122 cells, respectively. Concentrations ranging from 10 to 300 nM are sufficient for its action, which is hindered by the proteasome inhibitor MG-132. Demonstrating selectivity, AP-1 exhibits cytotoxicity towards ALK-dependent Karpas-299 cells with an IC50 value of 0.1265 nM, while showing significantly less toxicity to non-ALK-dependent THP-1 cells (IC50 = 2,704 nM). Furthermore, it effectively reduces tumor volume in NCI H3122 mouse xenograft models at doses of 25, 50, and 100 mg/kg.

Boc-C1-PEG3-C4-OBn (PROTAC Linker 15) is a PEG-based PROTAC linker employed in the synthesis of various PROTACs, including PROTAC SGK3 degrader-1. PROTACs are composed of two distinct ligands connected by a linker; one ligand binds to an E3 ubiquitin ligase, while the other specifically interacts with the target protein. By leveraging the intracellular ubiquitin-proteasome system, PROTACs can selectively degrade target proteins[1].

MS143, a potent AKT degrader (DC50=46 nM and GI50=0.8 µM in PC3 cells), effectively induces AKT degradation through the ubiquitin-proteasome system in both a concentration- and time-dependent manner, leading to the suppression of cancer cell growth [1].

PR-39 TFA, a natural peptide rich in proline and arginine with antibacterial properties, acts as a noncompetitive, reversible, and allosteric inhibitor of the proteasome. It specifically attaches to the α7 subunit of the proteasome, preventing the degradation of the NF-κB inhibitor IκBα through the ubiquitin-proteasome pathway. Additionally, PR-39 TFA promotes angiogenesis, suppresses inflammatory responses, and notably decreases myocardial infarct size in mice [1] [2].

Leptosphaerodione, a compound derived from the Remotididymella sp. fungus, functions as a potent inhibitor of the ubiquitin-proteasome system (UPS) and demonstrates cytotoxic effects in HeLa cells with an IC50 value of 3.2 μM, classifying it as an anti-tumor agent [1].