proteasome-in-1

Proteasome-IN-1 is an inhibitor of proteasome.

PARP-1/Proteasome-IN-1 (compound 42i) is a dual inhibitor of PARP-1 and the proteasome, demonstrating significant inhibitory effects on breast cancer. By downregulating the expression of BRCA1 and RAD51, it impairs homologous recombination repair and induces apoptosis (cellular death).

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

HM90822 is a novel synthetic apoptotic protein (IAP) antagonist that induces apoptosis in human pancreatic cancer cells through proteasome-dependent degradation of IAPs containing the BIR2/3 structural domain.HM90822 inhibits the expression of XIAP and cIAP1/2 proteins in HM822-sensitive Panc-1 and BxPC-3 cells, induces ubiquitylation of IAPs and promotes induces IAP ubiquitination and promotes proteasome-dependent IAP degradation.

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.

Radicicol (Monorden) is an antifungal antibiotic and a potent inhibitor of heat shock protein 90 (Hsp90), which leads to the degradation of Hsp90 by the proteasome by binding to its ATP-binding pocket. In addition, Radicicol inhibits the growth and proliferation of several tumor cell lines. It also has anti-malarial activity and acts as an inhibitor of adipose- and obesity-related proteins (FTO). Radicicol inhibits iNOS gene expression by blocking the p38 kinase signaling pathway and NF-kB/Rel

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

SPDP-C6-NHS ester is an alkyl/ether-based linker used in the synthesis of PROTACs. PROTAC molecules contain two ligands joined by a linker: one ligand recruits an E3 ubiquitin ligase and the other binds to a target protein. SPDP-C6-NHS ester enables selective degradation of target proteins by exploiting the ubiquitin-proteasome system.

Boc-C1-PEG3-C4-OBn (PROTAC Linker 15) is a PEG-based PROTAC linker used in the synthesis of various PROTACs, including PROTAC SGK3 degrader-1. PROTACs consist 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, enabling selective degradation of target proteins via the intracellular ubiquitin-proteasome system[1].

Boc-C1-PEG3-C4-OH is an Alkyl/ether-based PROTAC linker used in the synthesis of PROTACs, characterized by their structure of two distinct ligands tethered by a linker, with one ligand binding to an E3 ubiquitin ligase and the other to the target protein, facilitating targeted protein degradation through the ubiquitin-proteasome system [1].

Phthalimide-PEG3-C2-OTs (Compound 5) is a PROTAC linker composed of PEGs, utilized in the synthesis of various PROTACs that connect two distinct ligands through a linker. One ligand targets an E3 ubiquitin ligase, while the other targets the specific protein of interest, enabling selective protein degradation through the ubiquitin-proteasome system [1].

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].

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

(±)15-HETE is an eicosanoid compound that possesses intrinsic biological activities and serves as a key enzymatic precursor for the biosynthesis of numerous other biologically active lipid-derived derivatives; furthermore, this alkyl chain-based structure functions as a proteolysis-targeting chimera (PROTAC) linker utilized in the chemical synthesis of various PROTAC molecules designed for targeted protein degradation.

PROTAC 20S proteasome subunit β5 degrader 1 (compound 12f) serves as a targeted degrader of the 20S proteasome subunit β5, exhibiting a DC50 value of 0.11 μM in FaDu cells. This compound disrupts the cell cycle and promotes apoptosis (apoptosis), while inhibiting cell proliferation and migration in both FaDu and KM3 BTZ cells. It is applicable for research into resistance to Bortezomib in pharyngeal carcinoma and multiple myeloma.

PROTAC TRIB2 degrader-1 (Compound 5k) is a potent TRIB2 degrader that selectively induces TRIB2 degradation via the CRBN-dependent ubiquitin-proteasome pathway. It effectively inhibits cell proliferation and induces cell apoptosis (apoptosis), making it useful in cancer research.

TrxR EGFR-IN-1 (Compound L1Au2) is a TrxR EGFR inhibitor with activity against both gefitinib-sensitive and -resistant lung cancer, effectively suppressing tumor proliferation and promoting apoptosis. It enhances GPX4 degradation through autophagosome-lysosome and proteasome pathways, leading to ferroptosis. Additionally, it induces endoplasmic reticulum stress and triggers immunogenic cell death, making it applicable for studies on gefitinib-resistant lung cancer.

MS9024 is a degrader of DNA methyltransferase 1 (DNMT1), facilitating its degradation in HCT116 cells via the ubiquitin-proteasome pathway, with a DC50 of 35 nM (DC50 values are 254 nM in MDA-MB-468 and 101 nM in H1299). Additionally, MS9024 inhibits DNMT1 with an IC50 of 0.43 μM.

c-Met degrader-1 (Compound H11) is an orally active c-Met degrader that operates via the ubiquitin-proteasome system. It exhibits anti-hepatocellular carcinoma (HCC) activity and hampers tumor growth in MHCC97H xenografts. Additionally, c-Met degrader-1 suppresses the proliferation of HCC cells, disrupts the cell cycle, and induces apoptosis. It may also potentially overcome resistance to Type I c-Met inhibitors.

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.

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.

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).

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].

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.