TMU454
TMU454 is an ASGPR-targeting GalNAc-PROTAC BRD4 degrader conjugate. TMU454 undergoes ASGPR-mediated endocytosis and CTSB cleavage to release MZ1, which selectively degrades BRD4 in ASGPR-positive hepatocellular carcinoma cells via the VHL/UPS/proteasome pathway. TMU454 inhibits cancer cell proliferation and colony formation, and suppresses tumor growth in vivo. TMU454 can be used for research related to hepatocellular carcinoma.
(Pink: BRD4 ligand (HY-13030); Blue: VHL ligand (HY-125845); Black: linker (HY-140189)).
Para uso exclusivo en investigación. No vendemos a pacientes.
- Fòrmula: C142H214ClN27O44S2
- Peso molecular:3102.96
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Actividad biológica
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Chemical Information
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- Pureza y Documentación
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Actividad biológica
Descripciòn
IC50 & Target
[1]|
BRD4 |
In Vitro
TMU454 (0.01-1 μM; 1-24 h) preferentially degrades BRD4 in ASGPR-positive hepatocellular carcinoma cells (HepG2 and Huh7), while showing limited activity in ASGPR-negative cancer cells and normal cells[1].
TMU454 (1 μM; 12 h)-mediated BRD4 degradation depends on the ubiquitin-proteasome system in HepG2 and Huh7 cells[1].
TMU454 (1 μM; 12 h)-induced BRD4 degradation is reversible in HepG2 and Huh7 cells[1].
TMU454 (1 μM; 3 h) degrades BRD4 in HepG2 cells, and this activity is competitively inhibited by the tri-GalNAc ligand and attenuated by the endocytosis inhibitor MβCD, indicating that the entry of TMU454 and BRD4 degradation depend on ASGPR-mediated endocytosis[1].
TMU454 (48 h) exhibits antiproliferative activity against Huh7 cells with an IC50 of 481.9 nM[1].
TMU454 (1 μM; 3 days) inhibits the colony formation ability of Huh7 cells[1].
TMU454 (40 μM; 0.25-4 h) is efficiently cleaved by CTSB in vitro to release MZ1[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:HepG2, Huh7, DU145, HeLa, and HK-2
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Concentration:0.01, 0.03, 0.1, 0.3, 1 μM (HepG2, Huh7, DU145); 0.1 μM (HepG2, DU145); 0.1, 1 μM (HeLa, HK-2)
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Incubation Time:3 h (HepG2, Huh7, DU145); 1, 3, 6, 12, 24 h (HepG2, DU145); 12 h (HeLa, HK-2)
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Result:Effectively degraded BRD4 in a concentration-dependent manner in ASGPR-positive HepG2 and Huh7 cells and in a time-dependent manner in HepG2 cells.
Exhibited no noticeable BRD4 degradation in ASGPR-negative DU145 cells.
Demonstrated substantially lower BRD4 degradation in normal HK-2 cells.
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Cell Line:HepG2 and Huh7
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Concentration:1 μM
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Incubation Time:12 h
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Result:Co-treatment with MG132 completely abolished BRD4 degradation induced by TMU454 in both HepG2 and Huh7 cells.
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Cell Line:HepG2 and Huh7
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Concentration:1 μM
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Incubation Time:12 h
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Result:Following compound removal and incubation with fresh medium for an additional 12 h, BRD4 levels in both HepG2 and Huh7 cells were restored.
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Cell Line:HepG2
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Concentration:1 μM
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Incubation Time:3 h
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Result:Pretreatment with tri-GalNAc-alkyne significantly impaired TMU454-induced BRD4 degradation in HepG2 cells.\nMβCD substantially reduced TMU454's efficacy in degrading BRD4 in HepG2 cells.\nPretreatment with CA-074Me completely blocked TMU454-induced BRD4 degradation in HepG2 cells.
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Cell Line:Huh7
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Concentration:1 μM
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Incubation Time:3 days
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Result:Inhibited the colony-forming ability of Huh7 cells.
In Vivo
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:BALB/c nude mice (female, 4 weeks old)[1]
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Dosage:10 mg/kg
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Administration:i.p.; once daily; 7 days
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Result:Robustly suppressed tumor growth, outperforming the MZ1-treated groups, without inducing notable body weight loss.
Revealed no apparent toxicity in heart, liver, kidney, and spleen.
- BrdU Incorporation Assay
- Somatic Cell Culture
- CFSE Dye Dilution Proliferation Assay
- Dye-dilution cell tracking and proliferation staining
- Patient-Derived Orthotopic Xenograft (PDOX)
- CCK-8/WST-8 Cell Proliferation Assay
- Protocol for Cell Cycle
- Liver Cancer Modeling
- Cell Counting-Based Growth Curve Assay
- Colony Formation (Clonogenic) Assay
- Cell Viability Determination by MTT Colorimetric Assay
- EdU Incorporation Assay (Click Chemistry-Based DNA Synthesis Measurement)
- Ki-67 Immunostaining Proliferation Assay
- PCNA Immunodetection Proliferation Assay
- Protocol for Cell Counting and Cell Density Analysis
- Patient-Derived Xenograft (PDX)
- Soft Agar Colony Formation Assay
- MTT Cell Proliferation Assay
- Subcutaneous Cell-Line-Derived Xenograft
- Orthotopic Cell-Line Xenograft
Chemical Information
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Peso molecular 3102.96
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Fòrmula C142H214ClN27O44S2
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SMILES
OC[C@@H](O1)[C@H](O)[C@H](O)[C@@H](NC(C)=O)[C@@H]1OCCCCC(NCCCNC(CCOCC(COCCC(NCCCNC(CCCCO[C@H]2[C@H](NC(C)=O)[C@@H](O)[C@@H](O)[C@@H](CO)O2)=O)=O)(COCCC(NCCCNC(CCCCO[C@H]3[C@H](NC(C)=O)[C@@H](O)[C@@H](O)[C@@H](CO)O3)=O)=O)NC(CCCC4=CN(N=N4)CCOCCOCCC(N[C@@H](C(C)C)C(N[C@@H](CCCNC(N)=O)C(NC(C=C5)=CC=C5COC(O[C@@H](C6)C[C@@H](C(NCC7=CC=C(C8=C(C)N=CS8)C=C7)=O)N6C([C@H](C(C)(C)C)NC(COCCOCCOCCNC(C[C@H](N=C9C(C=C%10)=CC=C%10Cl)C%11=NN=C(C)N%11C%12=C9C(C)=C(C)S%12)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
TMU454 Related Classifications
HY-180909 Related Classifications
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Keywords
- TMU454
- TMU 454
- TMU-454
- PROTACs
- Epigenetic Reader Domain
- Asialoglycoprotein Receptor (ASGPR)
- hepatocellular carcinoma cells
- ASGPR-mediated endocytosis
- HepG2
- BRD4
- ASGPR
- liver cancer xenograft model
- UPS-dependent proteasomal degradation
- CTSB-mediated linker cleavage
- ubiquitin-proteasome system
- Huh7
- Inhibitor
- inhibitor
- inhibit