Pevonedistat (MLN4924) is a potent and selective, first-in-class inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy. MLN4924 (3 μM) inhibits overall protein turnover by <9% in HCT-116 cells. MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition. Expression of UBA3 A171T is sufficient to decrease MLN4924 sensitivity of naive HCT116 cells, indicating that it is a dominant suppressor of MLN4924-mediated cell death.
In vivo administration of Pevonedistat (MLN4924) to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, Pevonedistat (MLN4924) treatment resulted in NF-kappaB pathway inhibition accompanied by tumor regressions.
PLOS Genetics. 2018 Jan 25;14(1):e1007165.
CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory
Pevonedistat (MLN4924) purchased from AbMole
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Source | Plos One (2018). Figure6. MLN4924 (Abmole Bioscience) |
| Method | Western blot | |
| Cell Lines | CRBN KO cells | |
| Concentrations | 0.1 μM | |
| Incubation Time | 24 hrs | |
| Results | The BK currents were significantly decreased in CRBN-depleted cells compared to isogenic WT cells, and the difference was largely offset by treating the mutant cells with MLN4924 |
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Source | Plos One (2018). Figure5. MLN4924 (Abmole Bioscience) |
| Method | Western blot | |
| Cell Lines | CRBN KO glioma cells | |
| Concentrations | 0.2 μM | |
| Incubation Time | 24 hrs | |
| Results | Likewise, treatment with proteasome or neddylation inhibitors in CRBN KO glioma cells could also increase the Slo1 levels, though treatment with bortezomib or MLN4924 in WT cells for excessive time led to decreased Slo1 levels, likely due to compound cytotoxicity |
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Source | Oncol Lett (2018). Figure 3. MLN4924 |
| Method | immunofluorescence | |
| Cell Lines | EC1 and Kyse450 cells | |
| Concentrations | 0.0, 0.1, 0.2, 0.3, 0.4, 0.6, 0.8, 1.0 μM | |
| Incubation Time | 72 h | |
| Results | MLN4924 treatment increased the level of CDT1 and ORC1 proteins in a dose.dependent manner. |
| Cell Experiment | |
|---|---|
| Cell lines | HCT-116 cells |
| Preparation method | Cell viability assay. Cell suspensions were seeded at 3,000–8,000 cells per well in 96-well culture plates and incubated overnight at 37℃. Compounds were added to the cells in complete growth media and incubated for 72 h at 37℃. Cell number was quantified using the ATPlite assay (PerkinElmer). |
| Concentrations | 0~100µM |
| Incubation time | 72h |
| Animal Experiment | |
|---|---|
| Animal models | Female athymic NCR Mice bearing HCT-116 xenografts |
| Formulation | 10% cyclodextrin |
| Dosages | 10,30 or 60mg/kg |
| Administration | subcutaneously |
| Molecular Weight | 443.52 |
| Formula | C21H25N5O4S |
| CAS Number | 905579-51-3 |
| Solubility (25°C) | DMSO ≥ 50 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
| Related NEDD8-activating Enzyme Products |
|---|
| ZM223 hydrochloride
ZM223 hydrochloride is a potent, orally active, non-covalent NEDD8 activating enzyme (NAE) inhibitor. |
| NAE-IN-M22
NAE-IN-M22 is a potent, selective, and reversible inhibitor of NEDD8-activating enzyme (NAE) in the micromolar range. In addition, NAE-IN-M22 inhibits the growth of various cancer cells and induces apoptosis in A549 cells. |
| TAS4464 hydrochloride
TAS4464 (hydrochloride) is a highly potent and selective inhibitor of NEDD8 activating enzyme (NAE), with an IC50 of 0.955 nM. |
| Pevonedistat hydrochloride
Pevonedistat hydrochloride (MLN4924 hydrochloride) is a potent and selective NEDD8-activating enzyme (NAE) inhibitor, with an IC50 of 4.7 nM. |
| TAS4464
TAS4464 is a highly selective inhibitor of NEDD8 activated enzyme (NAE),IC50 The value is 0.955 nM. |
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