Mcl1 Degrader-1
Mcl1 Degrader-1 is an autophagy-targeting chimera (AUTAC) that selectively degrades the Mcl1 protein. Mcl1 Degrader-1 mediates K63 ubiquitination of Mcl1 via TRAF6/UBC13, transports it to autolysosomes for degradation through p62/SQSTM1, and activates Beclin1-dependent autophagy. Mcl1 Degrader-1 can be used in studies related to multiple myeloma and non-small cell lung cancer.
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- Formel: C51H54BrFN10O8S
- Molecular Weight:1066.00
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Please store the product under the recommended conditions in the Certificate of Analysis.
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Biologische Aktivität
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Chemical Information
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Biologische Aktivität
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Mcl-1 |
Mcl1 Degrader-1 (AUTAC) binds to Mcl1 selectively over Bcl2 and Bclxl[1].
Mcl1 Degrader-1 (100 nM-10 μM; 24-48 h) selectively degrades Mcl1 in a dose- and time-dependent manner in vitro in U266B1 cells, without degrading Bcl2 or Bclxl, while also activating autophagy[1].
Mcl1 Degrader-1 (5 μM; 24 h) requires autophagy to degrade Mcl1 in U266B1 cells[1].
Mcl1 Degrader-1 (0.1-10 μM; 24-72 h) reduces the viability and induces cell death of U266B1 and RPMI-8226 multiple myeloma cells in a time-dependent manner; its IC50 reaches 5 μM after 48 h of treatment in U266B1 cells[1].
Mcl1 Degrader-1 (10 μM; 24 h) dissociates Mcl1 from Beclin1 and increases the phosphorylation level of Beclin1 in U266B1 cells, thereby activating Beclin1-dependent autophagy[1].
Mcl1 Degrader-1 (5-10 μM; 16-24 h) promotes K63-linked ubiquitination of Mcl1 and its binding to p62/SQSTM1 in U266B1 cells, followed by colocalization with LC3B to achieve selective autophagic degradation[1].
Mcl1 Degrader-1 (5 μM; 24-72 h) degrades Mcl1 and triggers apoptotic cell death in U266B1 cells, and this biological process requires the participation of p62/SQSTM1, TRAF6 and UBC13. Genetic knockdown of these proteins completely abolishes the activity of this compound, which validates the above findings[1].
Mcl1 Degrader-1 (5 μM; 16–72 h) in combination with Carfilzomib (HY-10455) enhances Mcl1 degradation in U266B1 cells, a process dependent on NRF1, functional autophagy (via ATG5), and p62/SQSTM1[1].
Mcl1 Degrader-1 (500 nM-5 μM; 16-72 h) can be degraded by Carfilzomib through enhanced autophagic flux in wild-type and proteasome inhibitor-resistant multiple myeloma and NSCLC cells[1].
Mcl1 Degrader-1 (5 μM; 72 h) synergizes with Carfilzomib to reduce viability and induce apoptosis in wild-type and proteasome inhibitor-resistant multiple myeloma and non-small cell lung cancer (NSCLC) cells, and this synergy depends on p62/SQSTM1[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Cell Line:U266B1 multiple myeloma cells
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Concentration:100 nM, 500 nM, 1 μM, 5 μM, 10 μM (Mcl1 AUTAC);
5 μM (Mcl1 AUTAC, Mcl1-binding moiety); 10 μM (FBnG) -
Incubation Time:24 h, 48 h (Mcl1 AUTAC); 24 h (individual components, starvation)
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Result:Reduced Mcl1 protein levels in a dose- and time-dependent manner, with no observable effect on Bcl2 or Bclxl.
Increased LC3 I/II levels, indicating autophagy activation.
Showed no effect on Mcl1 expression when used as individual components; starvation-induced autophagy also did not reduce Mcl1 levels.
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Cell Line:U266B1 multiple myeloma cells, ATG5-knockdown U266B1 multiple myeloma cells
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Concentration:5 μM (Mcl1 AUTAC); 20 μM (CQ); 1 mM (3-MA)
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Incubation Time:24 h
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Result:Rescued Mcl1 degradation when combined with CQ or 3-MA.
Led to greater LC3II accumulation when combined with CQ compared to CQ alone.
Alleviated Mcl1 degradation in ATG5-knockdown cells.
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Cell Line:U266B1 and RPMI-8226 multiple myeloma cells
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Concentration:0.1, 0.5, 1, 5, 10 μM (Mcl1 AUTAC); 5 μM (Mcl1 AUTAC, Mcl1-binding moiety, FBnG)
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Incubation Time:24 h, 48 h, 72 h (Mcl1 AUTAC); 24 h (individual components, starvation)
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Result:Reduced cell viability in a time-dependent manner, with an IC50 of 5 μM after 48 h in U266B1 cells and 10 μM after 48 h in RPMI-8226 cells.
Induced approximately 50% cell death at 48 h and 60% at 72 h in U266B1 cells.
Caused robust accumulation of cleaved caspase 3 and cleaved PARP at 24 and 48 h.
Showed no caspase 3 cleavage when used as individual components; starvation also did not induce caspase 3 cleavage.
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Cell Line:U266B1 multiple myeloma cells
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Concentration:10 μM
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Incubation Time:24 h
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Result:Reduced the binding between Mcl1 and Beclin1.
Increased the phosphorylation of Beclin1.
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Cell Line:U266B1 multiple myeloma cells
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Concentration:5, 10 μM
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Incubation Time:16 h, 24 h
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Result:Induced clear colocalization of Mcl1 with K63-linked ubiquitin, p62/SQSTM1, and LC3B.
Increased the binding of Mcl1 to both K63-linked ubiquitin and p62/SQSTM1.
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Cell Line:U266B1 multiple myeloma cells, p62/SQSTM1-knockdown U266B1 multiple myeloma cells, TRAF6-knockdown U266B1 multiple myeloma cells, UBC13-knockdown U266B1 multiple myeloma cells
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Concentration:5 μM
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Incubation Time:24 h, 72 h
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Result:Abolished Mcl1 degradation and reduced accumulation of cleaved caspase 3 and cleaved PARP in p62/SQSTM1-knockdown cells.
Suppressed Mcl1 degradation and PARP cleavage in TRAF6 or UBC13-knockdown cells.
Reduced U266B1WT cell viability by over 50%, but blunted this cytotoxic response in p62/SQSTM1, TRAF6, or UBC13-knockdown cells.
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Cell Line:multiple myeloma (U266B1, MM.1S, RPMI-8226, AMO-1, U266B1R, AMO-1R) and non-small cell lung cancer (NCI-H1975, NCI-H1975R) cells
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Concentration:500 nM-5 μM (Mcl1 AUTAC); 2.5 nM, 10 nM (carfilzomib)
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Incubation Time:16 h, 24 h, 48 h, 72 h
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Result:Enhanced Mcl1 degradation across all tested cell lines, including proteasome inhibitor-resistant lines, when combined with CFZ.
Increased LC3I/II levels, indicating enhanced autophagic flux, when combined with CFZ.
Showed more pronounced reduction in Mcl1 levels, increased accumulation of LC3B and LAMP1, and greater colocalization of Mcl1 with these markers in U266B1 cells when combined with CFZ.
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Cell Line:U266B1 multiple myeloma cells, NRF1-knockout U266B1 multiple myeloma cells, ATG5-knockdown U266B1 multiple myeloma cells, p62/SQSTM1-knockdown U266B1 multiple myeloma cells
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Concentration:5 μM (Mcl1 AUTAC); 10 nM (carfilzomib)
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Incubation Time:16 h, 24 h, 72 h
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Result:Lost enhanced Mcl1 degradation by the Mcl1 AUTAC + CFZ combination in NRF1-knockout cells, with diminished LC3I/II levels.
Attenuated Mcl1 degradation by the Mcl1 AUTAC + CFZ combination in ATG5-knockdown cells.
Completely abolished Mcl1 degradation induced by the Mcl1 AUTAC + CFZ combination in p62/SQSTM1-knockdown cells.
Showed standalone Mcl1 degradation, autophagy induction, and cell death that were not dependent on NRF1.
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:NOD-SCID-IL2Rγ (NSG) (male and female, 4-6 weeks old, subcutaneous xenograft of U266B1 multiple myeloma cells)[1]
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Dosage:50 mg/kg
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Administration:i.p.; once daily; initiated on day 6 until study endpoint
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Result:Reduced mean tumor volume to ~300 mm3 compared to ~1200 mm3 for vehicle, ~500 mm3 for carfilzomib alone, and ~800 mm3 for monotherapy.
Reduced Mcl1/GAPDH ratio to ~0.7 vs ~1.0 for vehicle.
Increased LC3II/GAPDH ratio to ~1.4 vs ~1.0 for vehicle.
Showed no significant effect on Bcl2 or Bclxl levels.
Caused no significant changes in mouse body weight.
Chemical Information
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Molecular Weight 1066.00
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Formel C51H54BrFN10O8S
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SMILES
NC1=NC(C2=C(N(C(C3=CN(N=C3)CCCOCCOCCOCCCNC(CCCCC(NCCN4C(C5=CC=C(C6=CC=CC(C4=O)=C56)SC7=CC=C(C=C7)Br)=O)=O)=O)=N2)CC8=CC=C(C=C8)F)N1)=O
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Versand
Room temperature in continental US; may vary elsewhere.
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Speicherung
Please store the product under the recommended conditions in the Certificate of Analysis.
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Konzentration (Stammlösung) × Volumen (Stammlösung) = Konzentration (Ziellösung) × Volumen (Ziellösung)
Mcl1 Degrader-1 Related Classifications
HY-184160 Related Classifications
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