PEVONEDISTAT
Pevonedistat
CAS: 905579-51-3
Molecular Formula: C21H25N5O4S
PEVONEDISTAT - Names and Identifiers
PEVONEDISTAT - Physico-chemical Properties
| Molecular Formula | C21H25N5O4S |
| Molar Mass | 443.52 |
| Density | 1.62 |
| Melting Point | 161-163°C |
| Boling Point | 721.0±70.0 °C(Predicted) |
| Solubility | Soluble in DMSO (up to 10 mg/ml). |
| Appearance | Form solid, color White |
| Color | White |
| pKa | 9.35±0.70(Predicted) |
| Storage Condition | -20°C Freezer |
| Stability | Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20° for up to 3 months. |
| Physical and Chemical Properties | Bioactive Pevonedistat (MLN4924) is a small molecule inhibitor of Nedd8 activator enzyme (NAE) with an IC50 of 4 nM. |
| In vitro study | MLN4924 is structurally related to adenosine 59-phosphate (AMP) and is a tightly bound product of the NAE reaction. MLN4924 (3 μm) acts on HCT-116 cell lysate to selectively inhibit NAE. MLN4924 (3 μm) inhibited <9% of overall protein turnover in HCT-116 cells. MLN4924 acts on HCT-116 cells to reduce Ubc12-NEDD8 thioester and NEDD8-Cullin conjugate in a dose-dependent manner, with IC50<0.1 μm, resulting in CRL substrates CDT1, p27 and NRF2, rather than a large increase in non-CRL substrate. Treatment of HCT-116 cells with MLN4924(3 μm), at the early 8 hours, resulted in accumulation of cells in the S phase with a significant proportion of cells containing 4N DNA content at 24 hours. MLN4924 (3 μm) acts on ABC DLBCL cells, resulting in rapid accumulation of pIkappaBalpha, Reduction of nuclear p65 content, reduction of nuclear transcription factor-kappaB (NF-kappaB) transcriptional activity, and G(1) phase arrest ultimately lead to induction of apoptosis, consistent with effective inhibition of the NF-kappaB pathway. MLN4924 (1 μm) triggers DNA replication and inhibits cell proliferation by stabilizing DNA replication factor Cdt 1, a substrate for culins 1 and 4. MLN4924 (1 μm) was sufficient to elevate Cdt1 for up to 4-5 hours, to induce DNA replication, and to activate apoptosis and senescence pathways. MLN4924 treatment, which induces senescence phenotypic properties such as enlarged and flattened cell morphology, demonstrates senescence-associated β-gal staining positive. Mln4924-induced senescence is associated with a cellular response to DNA damage caused by the accumulation of DNA silencing proteins CDT1 and ORC1 as a result of inactivation of CRL/SCF E3s. Mln4924-induced senescence is irreversible, with a sustained accumulation of p21, and a sustained activation of the DNA damage response. |
| In vivo study | MLN4924 (60 mg/kg) treatment of HCT-116 tumor bearing mice reduced the level by NEDD8-cullin in the early 30 minutes, in a dose and time dependent manner, and the maximal effect was maintained after 1-2 hours of treatment. MLN4924 (60 mg/kg) increased the steady-state levels of NRF2 and CDT1 in HCT-116 tumor-bearing mice in a dose-and time-dependent manner. MLN4924 (60 mg/kg) MLN4924 (60 mg/kg) acts on HCT-116 tumor-bearing mice, causing DNA damage and increasing phosphorylated CHK1 levels. MLN4924 inhibits tumor growth in HCT-116 tumor-bearing mice treated twice daily at 30 mg/kg and 60 mg/kg BID schedule, the T/C values were 0.36 and 0.15, respectively. MLN4924 (60 mg/kg) treatment of mice bearing human xenograft ABC-and GCB-DLBCL inhibited NAE pathway biomarkers and completely inhibited tumor growth. MLN4924 (60 mg/kg) treatment of mice bearing human xenograft ABC-DLBCL inhibited the NF-kappaB pathway with concomitant tumor regression. |
PEVONEDISTAT - Preparation solution concentration reference
| 1mg | 5mg | 10mg | |
|---|---|---|---|
| 1 mM | 2.255 ml | 11.273 ml | 22.546 ml |
| 5 mM | 0.451 ml | 2.255 ml | 4.509 ml |
| 10 mM | 0.225 ml | 1.127 ml | 2.255 ml |
| 5 mM | 0.045 ml | 0.225 ml | 0.451 ml |
Last Update：2024-01-02 23:10:35
PEVONEDISTAT - Reference Information
| biological activity | Pevonedistat (MLN4924) is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with an IC50 of 4 nM. |
| Target | TargetValue NAE (Cell-free assay) 4 nM |
| Target | Value |
| NAE (Cell-free assay) | 4 nM |
| in vitro study | MLN4924 is structurally related to adenosine 59-phosphate (AMP), is the tightly bound product of the NAE reaction. MLN4924 (3 μm) acts on HCT-116 cell lysate to selectively inhibit NAE. MLN4924 (3 μm) inhibited <9% of overall protein turnover in HCT-116 cells. MLN4924 acts on HCT-116 cells to reduce Ubc12-NEDD8 thioester and NEDD8-Cullin conjugate in a dose-dependent manner, with IC50<0.1 μm, resulting in CRL substrates CDT1, p27 and NRF2, rather than a large increase in non-CRL substrate. Treatment of HCT-116 cells with MLN4924(3 μm), at the early 8 hours, resulted in accumulation of cells in the S phase with a significant proportion of cells containing 4N DNA content at 24 hours. MLN4924 (3 μm) acts on ABC DLBCL cells, resulting in rapid accumulation of pIkappaBalpha, decreased nuclear p65 content, decreased nuclear transcription factor-kappaB (NF-kappaB) transcriptional activity, and G(1). Phase arrest, which ultimately leads to induction of apoptosis, is consistent with effective inhibition of the NF-kappaB pathway. MLN4924 (1 μm) triggers DNA replication and inhibits cell proliferation by stabilizing DNA replication factor Cdt 1, a substrate for culins 1 and 4. MLN4924 (1 μm) is sufficient to raise Cdt1 for up to 4-5 hours, is sufficient to induce DNA replication, and activates apoptosis and senescence pathways. MLN4924 treatment, which induces senescence phenotypic properties such as enlarged and flattened cell morphology, demonstrates senescence-associated β-gal staining positive. Mln4924-induced senescence is associated with a cellular response to DNA damage caused by the accumulation of DNA silencing proteins CDT1 and ORC1 as a result of inactivation of CRL/SCF E3s. Mln4924-induced senescence is irreversible, with a sustained accumulation of p21, and a sustained activation of the DNA damage response. |
| in vivo study | MLN4924 (60 mg/kg) treated HCT-116 tumor bearing mice, this effect was dose-and time-dependent with a NEDD8-cullin reduction in levels, and the maximal effect was maintained after 1-2 hours of treatment. MLN4924 (60 mg/kg) increased the steady-state levels of NRF2 and CDT1 in HCT-116 tumor-bearing mice in a dose-and time-dependent manner. MLN4924 (60 mg/kg) MLN4924 (60 mg/kg) acts on HCT-116 tumor-bearing mice, causing DNA damage and increasing phosphorylated CHK1 levels. MLN4924 inhibits tumor growth in HCT-116 tumor-bearing mice treated twice daily at 30 mg/kg and 60 mg/kg BID schedule, the T/C values were 0.36 and 0.15, respectively. MLN4924 (60 mg/kg) treatment of mice bearing human xenograft ABC-and GCB-DLBCL inhibited NAE pathway biomarkers and completely inhibited tumor growth. MLN4924 (60 mg/kg) treatment of mice bearing human xenograft ABC-DLBCL inhibited the NF-kappaB pathway with concomitant tumor regression. |
Last Update：2024-04-10 22:29:15
PEVONEDISTAT - Nature
| Solubility | Soluble in DMSO (up to 10 mg/ml). |
Last Update：2024-04-10 22:29:15
PEVONEDISTAT - Uses and synthesis methods
Target
Target Value
NAE
(Cell-free assay) 4 nM
in vitro studies
MLN4924 is structurally related to 59-adenosine phosphate (AMP) and is a tight binding product of the NAE reaction. MLN4924 (3 μM) acts on HCT-116 cell lysate to selectively inhibit NAE. MLN4924 (3 μM) acts on HCT-116 cells and inhibits <9% of overall protein turnover. MLN4924 acts on HCT-116 cells to reduce the conjugate of Ubc12-NEDD8 thioester and NEDD8-Cullin. This effect is dose-dependent, IC50<0.1 μM, which greatly increases CRL substrates CDT1, p27 and NRF2 instead of non-CRL substrates. MLN4924(3 μM) treatment of HCT-116 cells resulted in the accumulation of cells in the S phase at the early 8 hours and a significant proportion of cells containing 4N DNA at 24 hours. MLN4924 (3 μM) acts on ABC DLBCL cells, resulting in rapid accumulation of pIkappaBalpha, reduction of nuclear p65 content, reduction of nuclear transcription factor-kappaB (NF-kappaB) transcription activity, and G(1) phase arrest, eventually leading to induction of apoptosis, which is consistent with effective inhibition of NF-kappaB pathways. MLN4924 (1 μM) triggers DNA replication and inhibits cell proliferation by stabilizing DNA replication factor Cdt 1, which is a substrate for cullins 1 and 4. MLN4924 (1 μM) is enough to promote Cdt1 for 4-5 hours, enough to induce DNA replication, and activate apoptosis and aging pathways. MLN4924 treatment, induced aging phenotype characteristics, such as magnified and flattened cell morphology, proved positive β-Gal staining related to aging. MLN4924-induced senescence is related to cell response to DNA damage, which is caused by the accumulation of DNA silencing proteins CDT1 and ORC1 and is the result of inactivation of CRL/SCF E3s. MLN4924-induced aging is irreversible, accompanied by continuous accumulation of p21 and continuous activation of DNA damage response.
In vivo studies
MLN4924 (60 mg/kg) treatment of mice carrying HCT-116 tumors reduces NEDD8-cullin levels in the early 30 minutes. this effect is dose-and time-dependent, and the maximum effect is maintained after 1-2 hours of treatment. MLN4924 (60 mg/kg) acts on mice carrying HCT-116 tumors to increase the steady-state levels of NRF2 and CDT1. This effect is dose-and time-dependent. MLN4924 (60 mg/kg) MLN4924 (60 mg/kg) acts on mice carrying HCT-116 tumors, causing DNA damage and increasing phosphorylated CHK1 level. MLN4924 mice carrying HCT-116 tumors were treated at 30 mg/kg and 60 mg/kg doses according to BID schedule. The mice were treated twice a day to inhibit tumor growth. The T/C values were 0.36 and 0.15 respectively. MLN4924 (60 mg/kg) treated mice carrying human transplanted tumor ABC-and GCB-DLBCL, inhibited NAE pathway biomarkers and completely inhibited tumor growth. MLN4924 (60 mg/kg) treated mice carrying human transplanted tumor ABC-DLBCL, which inhibited NF-kappaB pathway and accompanied tumor decline.
Last Update：2024-04-09 21:54:55
Supplier List
Spot supply
Product Name: MLN4924 Visit Supplier Webpage Request for quotationCAS: 905579-51-3
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
Wechat: 18301782025
Spot supply
Product Name: MLN4924 Visit Supplier Webpage Request for quotationCAS: 905579-51-3
Tel: 18301782025
Email: 3008007409@qq.com
Mobile: 18021002903
QQ: 3008007409
Wechat: 18301782025
View History