MLN4924 (Pevonedistat)

製品コード：S7109 純度：99.99%

MLN4924は、Nedd8活性化酵素（NAE）の低分子阻害剤であり、IC50は4 nMです。

CAS No. 905579-51-3

サイズ	価格(税別)	在庫状況
10mM (1mL in DMSO)	JPY 53800	国内在庫あり
2mg	JPY 22000	国内在庫あり
5mg	JPY 40000	国内在庫あり
25mg	JPY 104500	国内在庫なし(納期7~10日)
100mg	JPY 220500	国内在庫あり
1g	JPY 745500	国内在庫なし(納期7~10日)

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文献中Selleckの製品使用例（152）

製品安全説明書

現在のバッチを見る：純度： 99.99%

99.99

MLN4924 (Pevonedistat)関連製品

関連製品	TAK-243 (MLN7243) PYR-41 ML792 Pevonedistat hydrochloride Ubiquitin Antibody (Rabbit mAb) [J9C13] TAS4464 COH000 DKM 2-93	もっと見る
関連化合物ライブラリー	Kinase Inhibitor Library FDA-approved Drug Library Natural Product Library Bioactive Compound Library-I Highly Selective Inhibitor Library	もっと見る

シグナル伝達経路

E1 Activatingシグナル伝達経路

E1 Activating阻害剤の選択性比較

Cell Data

Cell Lines	Assay Type	Incubation Time	活性情報	PMID
K562	Antiproliferative assay	72 hrs	Antiproliferative activity against human K562 cells after 72 hrs by CellTiter-Glo assay, EC50 = 0.108 μM.	24900352
U2OS	Antitumor assay	72 hrs	Antitumor activity against human U2OS cells after 72 hrs by MTT assay, IC50 = 0.16 μM.	28388520
HCT116	Antitumor assay	72 hrs	Antitumor activity against human HCT116 cells after 72 hrs by MTT assay, IC50 = 0.19 μM.	28388520
Caco2	Function assay	16 hrs	Inhibition of NAE-mediated Ubcl2-NEDD8 conjugation in human Caco2 cells after 16 hrs by Western blot analysis, EC50 = 3.4 μM.	29232579
Caco2	Function assay	16 hrs	Inhibition of NAE-mediated Ubcl2-NEDD8 conjugation in human Caco2 cells after 16 hrs by Western blot analysis, EC50 = 3.4 μM.	29232579
Caco2	Cytotoxicity assay	72 hrs	Cytotoxicity against human Caco2 cells after 72 hrs by MTT assay, IC50 = 4.4 μM.	29232579
他の多くの細胞株試験データをご覧になる場合はこちらをクリックして下さい

生物活性

製品説明

MLN4924は、Nedd8活性化酵素（NAE）の低分子阻害剤であり、IC50は4 nMです。

特性

A mechanism-based inhibitor of NAE, and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme.

Targets

NAE
(Cell-free assay)

4 nM

In Vitro
In vitro	Pevonedistat (MLN4924) is structurally related to adenosine 59-monophosphate (AMP)—a tight binding product of the NAE reaction. It (3 μM) selectively inhibits NAE in HCT-116 cell lysates and inhibits overall protein turnover by <9% in HCT-116 cells. This compound 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. It (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. At the same concentration, it 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. At 1 μM, it triggers DNA replication and inhibits cell proliferation by stabilizing the DNA replication factor Cdt1, a substrate of cullins 1 and 4. This concentration, 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. Treatment with this compound 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. It is irreversible and coupled with persistent accumulation of p21 and sustained activation of DNA damage response.
Kinase Assay	In vitro E1-activating enzyme assays
Kinase Assay	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.
細胞実験	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 ℃. Pevonedistat (MLN4924) is then added to the cells in complete growth media and incubated for 72 hours at 37 ℃. Cell number is quantified using the ATPlite assay.
実験結果図	Methods	Biomarkers	結果図	PMID
	Western blot	Culin 3 / CDT2 / CDT1 / SET8 / p21 / p-p53 / p-CHK1 / p-CHK2 / CHK2 / γH2AX / H2AX / PARP / c-PARP Culin 1 / WEE1 / p27 / p-H3 / cyclin B1 Cleaved caspase-3 / Cleaved PARP pro-apoptotic and anti-apoptotic proteins p-c-Jun / c-Jun p-H2A / p-CHK2 p-AKT / p-mTOR / p-70S6K		28838998
	Immunofluorescence	RhoB / VE-cadherin / F-actin		29358211
	Growth inhibition assay	Cell viability		27333051

In Vivo
In Vivo	Pevonedistat (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. It also leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice. This compound leads to DNA damage in the tumour indicated by the increased levels of phosphorylated CHK1 in HCT-116 tumour-bearing mice. When administered on a BID schedule at 30 mg/kg and 60 mg/kg, it inhibits tumour growth with T/C values of 0.36 and 0.15, respectively, in mice bearing HCT-116 xenografts. It (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. This compound (60 mg/kg) results in NF-kappaB pathway inhibition accompanied by tumor regressions in primary human tumor mice models of ABC-DLBCL.
動物実験	動物モデル	mice bearing HCT-116 xenografts
	投与量	60 mg/kg
	投与経路	Subcutaneously injection

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
臨床試験 (data from https://clinicaltrials.gov, updated on 2026-09-03)
NCT03013998	RECRUITING	Previously Untreated Relapsed Refractory Acute Myeloid Leukemia	Beat AML, LLC	2016-11	PHASE2; PHASE3
NCT03862157	ACTIVE_NOT_RECRUITING	Acute Myeloid Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Eosinophilic Leukemia, Not Otherwise Specified; Chronic Myelomonocytic Leukemia; Chronic Neutrophilic Leukemia; Essential Thrombocythemia; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm With Ring Sideroblasts and Thrombocytosis; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Myeloid Neoplasm; Myeloproliferative Neoplasm; Myeloproliferative Neoplasm, Unclassifiable; Overt Primary Myelofibrosis; Polycythemia Vera; Polycythemia Vera, Post-Polycythemic Myelofibrosis Phase; Prefibrotic/Early Primary Myelofibrosis	M.D. Anderson Cancer Center	2019-02-27	PHASE1; PHASE2
NCT03330821	ACTIVE_NOT_RECRUITING	Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome; Acute Myeloid Leukemia With Myelodysplasia-Related Changes; Therapy-Related Acute Myeloid Leukemia	University of Southern California	2018-04-18	PHASE1; PHASE2
NCT03479268	ACTIVE_NOT_RECRUITING	B-Cell Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Diffuse Large B-Cell Lymphoma; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Mantle Cell Lymphoma; Refractory Marginal Zone Lymphoma; Refractory Non-Hodgkin Lymphoma; Refractory Small Lymphocytic Lymphoma; Richter Syndrome	City of Hope Medical Center	2018-04-27	PHASE1
NCT03009240	COMPLETED	Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Therapy-Related Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia	City of Hope Medical Center	2017-08-21	PHASE1
NCT04985656	WITHDRAWN	Myelodysplastic Syndromes (MDS)	Takeda	2021-10-01	PHASE2

参考
https://pubmed.ncbi.nlm.nih.gov/19360080/ https://pubmed.ncbi.nlm.nih.gov/20525923/ https://pubmed.ncbi.nlm.nih.gov/21159650/ https://pubmed.ncbi.nlm.nih.gov/21677879/ + 展開

参考

https://pubmed.ncbi.nlm.nih.gov/19360080/
https://pubmed.ncbi.nlm.nih.gov/20525923/
https://pubmed.ncbi.nlm.nih.gov/21159650/

https://pubmed.ncbi.nlm.nih.gov/21677879/

+ 展開

化学情報

分子量	443.52	化学式	C₂₁H₂₅N₅O₄S
CAS No.	905579-51-3	SDF	Download MLN4924 (Pevonedistat) SDFをダウンロードする
Smiles	C1CC2=CC=CC=C2C1NC3=C4C=CN(C4=NC=N3)C5CC(C(C5)O)COS(=O)(=O)N
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	1年-80°Cin solvent
保管	3年-20°C粉	溶液の保管冷凍と解凍の繰り返しを避けるため小分けにしてください	１ケ月-20°Cin solvent

In vitro
Batch:

DMSO : 89 mg/mL ( (200.66 mM)；吸湿したDMSOは溶解度を減少させます。新しいDMSOをご使用ください。)

Ethanol : 89 mg/mL

Water : Insoluble

モル濃度計算器

in vivo Batch: Add solvents to the product individually and in order.				投与溶液組成計算機
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.
Clear solution	5% DMSO 1 30% PEG 300 2 5% Tween 80 3 ddH2O この製剤はselleckのラボで検証済みです。上記の溶解方法がご要望を満たさない場合、selleckの営業担当までお問い合わせ頂ければ、個別の試験を行います。	4.000mg/ml (9.02mM)	Taking the 1 mL working solution as an example, add 50 μL of 80 mg/ml clarified DMSO stock solution to 300 μL of PEG300, mix evenly to clarify it; add 50 μL Tween-80 to the above system, mix evenly to clarify it; Then continue to add 600 μL ddH2O to adjust the volume to 1 mL. The mixed solution should be used immediately for optimal results.
Homogeneous suspension	CMC-NA	≥5mg/ml	Taking the 1 mL working solution as an example, add 5 mg of this product to 1 ml of CMC-Na solution, mix evenly to obtain a homogeneous suspension with a final concentration of 5 mg/ml.

実験計算

モル濃度計算器

質量	濃度	体積	分子量
=	×	×

希釈計算器分子量計算器

投与溶液組成計算機(クリア溶液)

ステップ１：実験データを入力してください。（実験操作によるロスを考慮し、動物数を1匹分多くして計算・調製することを推奨します）

投与量 mg/kg 動物平均体重 g 投与体積（動物毎）μL 動物数匹

ステップ２：投与溶媒の組成を入力してください。（ロット毎に適した溶解組成が異なる場合があります。詳細については弊社までお問い合わせください）

% DMSO + % + % Tween 80 + % ddH₂O

%DMSO+ %

計算結果：

投与溶媒濃度： mg/ml;

DMSOストック溶液調製方法： mg 試薬を μL DMSOに溶解する（濃度 mg/mL, 注：濃度が当該ロットのDMSO溶解度を超える場合はご連絡ください。 )

投与溶媒調製方法：Take μL DMSOストック溶液に μL PEG300，を加え、完全溶解後μL Tween 80，を加えて完全溶解させた後 μL ddH₂O，を加え完全に溶解させます。

投与溶媒調製方法：μL DMSOストック溶液に μL Corn oil，を加え、完全溶解。

注意：１.ストック溶液に沈殿、混濁などがないことをご確認ください；
２.順番通りに溶剤を加えてください。次のステップに進む前に溶液に沈殿、混濁などがないことを確認してから加えてください。ボルテックス、ソニケーション、水浴加熱など物理的な方法で溶解を早めることは可能です。

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