MLN4924

SKU: orb1300861

Description

Pevonedistat (MLN4924) is a selective NEDD8-activating enzyme (NAE) inhibitor with an IC50 of 4.7 nM. It exhibits antitumor activity and has been investigated for treating myelodysplastic syndromes (MDS) in clinical research, supported by studies demonstrating its efficacy in both in vitro and in vivo cancer models.

Research Area

Cell Biology, Molecular Biology, Neuroscience, Protein Biochemistry

Key Properties

• CAS Number: 905579-51-3
• MW: 443.53
• Purity: >98%
• Formula: C₂₁H₂₅N₅O₄S
• SMILES: N(C1=C2C(N(C=C2)[C@@H]3C[C@@H](COS(N)(=O)=O)[C@@H](O)C3)=NC=N1)[C@@H]4C=5C(CC4)=CC=CC5
• Target: Neddylation
• Solubility: Soluble in DMSO (up to 10 mg/ml).

Bioactivity

• Target IC50:
  CAPAN-1 cells:101 nM|EKVX cells:0.3 μM|HGC-27 cells:1.25 μM|DU-145 cells:201 nM|Neuroblastoma:136-400 nM|Huh7 cells:0.3 μM|HT29 cells:484 nM|BEAS-2B cells:1.22 μM|A549 cells:0.63 μM|GES1 cells:13.45 μM|HepG2 cells:0.3 μM|HuTu80 cells:42.6 nM|HCT116 cells:33.89 nM|Caco-2 cells:4.4 μM|NAE:4.7 nM
• In Vivo:
  METHODS: To detect anti-tumor activity in vivo, Pevonedistat (30-60 mg/kg in 10% cyclodextrin) was injected subcutaneously into BALB/c mice harboring the human colorectal cancer tumor HCT-116 either once or twice daily for twenty days. RESULTS: Pevonedistat inhibited the growth of HCT-116 xenograft tumors. METHODS: To assay in vivo antitumor activity, Pevonedistat (60 mg/kg, intraperitoneal injection, once daily), venetoclax (50 mg/kg, oral administration, once daily), and azacitidine (8 mg/kg, intravenously three times every seven days) were administered to NSGS mice harboring the AML tumor OCI-AML2-Red- Fluc for fourteen days. RESULTS: Pevonedistat/venetoclax/azacitidine triple therapy induced durable responses in a systemic xenograft model of acute myeloid leukemia.
• In Vitro:
  METHODS: Nine neuroblastoma cell lines were treated with Pevonedistat (12-1000 nM) for 72 h. Cell viability was measured by MTT. RESULTS: All neuroblastoma cell lines tested were sensitive to Pevonedistat with IC50 values ranging from 136-400 nM. METHODS: Human colorectal cancer cells HCT-116 were treated with Pevonedistat (0.001-3 μM) for 24 h, and the expression levels of target proteins were detected by Western Blot. RESULTS: Pevonedistat treatment resulted in a dose-dependent decrease in Ubc12-NEDD8 thioester and NEDD8-cullin couplings, leading to an increase in the abundance of known CRL substrates CDT1, p27 and NRF2.
• Cell Research:
  MLN4924 is dissolved in DMSO and stored, and then diluted with appropriate medium before use. HCT-116 cells grown in 6-well cell-culture dishes are treated with 0.1% DMSO (control) or 0.3 μM MLN4924 for 24 h. Whole cell extracts are prepared and analysed by immunoblotting. For analysis of the E2-UBL thioester levels, lysates are fractionated by non-reducing SDS-PAGE and immunoblotted with polyclonal antibodies to Ubc12, Ubc9 and Ubc10. For analysis of other proteins, lysates are fractionated by reducing SDS-PAGE and probed with primary antibodies as follows: mouse monoclonal antibodies to CDT1, p27, geminin, ubiquitin, securin/PTTG and p53 or rabbit polyclonal antibodies to NRF2, Cyclin B1 and GADD34.

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Pevonedistat

Compound Identifiers

PubChem CID

91885500