Pevonedistat (MLN4924)

製品コードS7109 バッチS710906

印刷

化学情報

Chemical Structure Synonyms Storage
(From the date of receipt)		 3 years -20°C powder
1 years -80°C in solvent
化学式

C21H25N5O4S
分子量 443.52 CAS No. 905579-51-3
Solubility (25°C)* 体外 DMSO 89 mg/mL (200.66 mM)
Ethanol 89 mg/mL (200.66 mM)
Water Insoluble
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明 MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.
in vitro MLN4924 is structurally related to adenosine 59-monophosphate (AMP)—a tight binding product of the NAE reaction. MLN4924 (3 μM) selectively inhibits NAE in HCT-116 cell lysates. MLN4924 (3 μM) inhibits overall protein turnover by <9% in HCT-116 cells. MLN4924 results in a dose-dependent decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates with an IC50 < 0.1 μM in HCT-116 cells, resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2, but not non-CRL substrates. MLN4924 (3 μM) leads cells to accumulate in S-phase as early as 8 hours and results in a significant fraction of cells contained 4N DNA content by 24 hours in HCT-116 cells. [1] MLN4924 (3 μM) results 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 in ABC DLBCL cells. [2] MLN4924 (1 μM) triggers DNA replication and inhibit cell proliferation by stabilizing the DNA replication factor Cdt1, a substrate of cullins 1 and 4. MLN4924 (1 μM) , which is sufficient to elevate Cdt1 for 4-5 hours, is found to be sufficient to induce DNA replication and to activate apoptosis and senescence pathways. [3] MLN4924 treatment induces the characteristics of senescence phenotypes as evidenced by enlarged and flattened cellular morphology and positive staining of senescence-associated β-Gal. MLN4924-induced senescence is associated with cellular response to DNA damage, triggered by accumulation of DNA-licensing proteins CDT1 and ORC1, as a result of inactivation of CRL/SCF E3s. MLN4924-induced senescence is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response. [4]
in vivo MLN4924 (60 mg/kg) results in a dose- and time-dependent decrease of NEDD8–cullin levels as early as 30 min after administration in HCT-116 tumour-bearing mice, with maximal effect 1–2 hours post-dose. MLN4924 (60 mg/kg) also leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice. MLN4924 (60 mg/kg) leads to DNA damage in the tumour indicated by the increased levels of phosphorylated CHK1 in HCT-116 tumour-bearing mice. MLN4924 administered on a BID schedule at 30 mg/kg and 60 mg/kg inhibits tumour growth with T/C values of 0.36 and 0.15, respectively, in mice bearing HCT-116 xenografts. [1] MLN4924 (60 mg/kg) blocks NAE pathway biomarkers and results in complete tumor growth inhibition in mice bearing human xenograft tumors of ABC- and GCB-DLBCL. MLN4924 (60 mg/kg) results in NF-kappaB pathway inhibition accompanied by tumor regressions in primary human tumor mice models of ABC-DLBCL. [2]
特徴 A mechanism-based inhibitor of NAE, and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme.

プロトコル(参考用のみ)

キナーゼアッセイ In vitro E1-activating enzyme assays
A time-resolved fluorescence energy transfer assay format is used to measure the in vitro activity of NAE. The enzymatic reaction, containing 50 μL 50 mM HEPES, pH 7.5, 0.05% BSA, 5 mM MgCl2, 20 μM ATP, 250 μM glutathione, 10 nM Ubc12–GST, 75 nM NEDD8–Flag and 0.3 nM recombinant human NAE enzyme, is incubated at 24 ℃ for 90 min in a 384-well plate, before termination with 25 μL of stop/detection buffer (0.1 M HEPES, pH 7.5, 0.05% Tween20, 20 mM EDTA, 410 mM KF, 0.53 nM Europium-Cryptate-labelled monoclonal Flag-M2-specific antibody and 8.125 μg/mL PHYCOLINK allophycocyanin (XL-APC)-labelled GST-specific antibody. After incubation for 2 hours at 24 ℃, the plate is read on the LJL Analyst HT Multi-Mode instrument using a time-resolved fluorescence method. A similar assay protocol is used to measure other E1 enzymes.
細胞アッセイ 細胞株 HCT-116 cells
濃度 3 μM
反応時間 72 hours
実験の流れ Cell suspensions are seeded at 3,000–8,000 cells per well in 96-well culture plates and incubated overnight at 37 ℃. MLN4924 are added to the cells in complete growth media and incubated for 72  hours at 37 ℃. Cell number is quantified using the ATPlite assay.
動物実験 動物モデル mice bearing HCT-116 xenografts
投薬量 60 mg/kg
投与方法 Subcutaneously injection

カスタマーフィードバック

Data from [Data independently produced by , , Leukemia, 2019, 33(1):171-180]

Data from [Data independently produced by , , J Exp Clin Cancer Res, 2018, 37(1):165]

Data from [Data independently produced by , , J Immunol, 2016, 196(7):3117-23]

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins [ Nat Commun, 2024, 15(1):2485] PubMed: 38509117
Mitochondrial outer membrane integrity regulates a ubiquitin-dependent and NF-κB-mediated inflammatory response [ EMBO J, 2024, 43(6):904-930] PubMed: 38337057
Inhibiting neddylation with MLN4924 potentiates hypoxia-induced apoptosis of mouse type B spermatogonia GC-2 cells [ Gene, 2024, 893:147935] PubMed: 38381506
Etoposide-induced SENP8 confers a feed-back drug resistance on acute lymphoblastic leukemia cells [ Biochem Biophys Rep, 2024, 37:101650] PubMed: 38314144
Identification of the main barriers to Ku accumulation in chromatin [ bioRxiv, 2024, 2024.01.03.574002] PubMed: 38260538
K6-linked ubiquitylation marks formaldehyde-induced RNA-protein crosslinks for resolution [ Mol Cell, 2023, 10.1016/j.molcel.2023.10.011] PubMed: 37951215
A central role for regulated protein stability in the control of TFE3 and MITF by nutrients [ Mol Cell, 2023, 83(1):57-73.e9] PubMed: 36608670
STING Suppresses Mitochondrial VDAC2 to Govern RCC Growth Independent of Innate Immunity [ Adv Sci (Weinh), 2023, 10(3):e2203718] PubMed: 36445063
BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels [ Proc Natl Acad Sci U S A, 2023, 120(39):e2305092120] PubMed: 37722046
CUL4B-DDB1-COP1-mediated UTX downregulation promotes colorectal cancer progression [ Exp Hematol Oncol, 2023, 12(1):77] PubMed: 37679762

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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