MLN4924
mRNA synthesis
In vitro transcription of capped mRNA with modified nucleotides and Poly(A) tail
Tyramide Signal Amplification (TSA)
TSA (Tyramide Signal Amplification), used for signal amplification of ISH, IHC and IC etc.
Phos Binding Reagent Acrylamide
Separation of phosphorylated and non-phosphorylated proteins without phospho-specific antibody
Cell Counting Kit-8 (CCK-8)
A convenient and sensitive way for cell proliferation assay and cytotoxicity assay
SYBR Safe DNA Gel Stain
Safe and sensitive stain for visualization of DNA or RNA in agarose or acrylamide gels.
Inhibitor Cocktails
Protect the integrity of proteins from multiple proteases and phosphatases for different applications.
MLN4924是一种有效的和选择性的NEDD8激活酶(NAE)抑制剂,IC50值为4 nM[1]。
MLN4924与AMP竞争结合NAE的核苷酸结合位点。与密切相关的酶UAE、SAE、UBA6和ATG7(IC50值分别为1.5、8.2、1.8和10 μM)相比,MLN4924对NAE具有高选择性。MLN4924对其它利用ATP的酶没有作用。在HCT-116细胞中,MLN4924导致Ubc12-NEDD8硫酯和NEDD8-滞蛋白(cullin)缀合物的减少,从而抑制CRL-泛素化介导的蛋白降解(比如CDT1蛋白),CDT1蛋白的积累会引起细胞周期缺陷。在HCT-116异种移植小鼠中,MLN4924以30 mg/kg和60 mg/kg的剂量显著抑制肿瘤生长,这些剂量的耐受性良好。在H522和Calu-6肺癌异种移植小鼠中,MLN4924也具有抗肿瘤活性[1]。
参考文献:
[1] Soucy TA, Smith PG, Milhollen MA, Berger AJ, Gavin JM, Adhikari S, Brownell JE, Burke KE, Cardin DP, Critchley S, Cullis CA, Doucette A, Garnsey JJ, Gaulin JL, Gershman RE, Lublinsky AR, McDonald A, Mizutani H, Narayanan U, Olhava EJ, Peluso S, Rezaei M, Sintchak MD, Talreja T, Thomas MP, Traore T, Vyskocil S, Weatherhead GS, Yu J, Zhang J, Dick LR, Claiborne CF, Rolfe M, Bolen JB, Langston SP. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6.
- 1. Tiantian Xu, Qisheng Ma, et al. "A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer." Signal Transduct Target Ther. 2022 Oct 17;7(1):354. PMID: 36253371
- 2. Fang Liu, Xuan Wang, et al. "A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells." Adv Sci (Weinh). 2022 Aug;9(22):e2104823. PMID: 35652200
- 3. Qiyin Zhou, Wenyu Lin, et al. " Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells." Nat Commun. 2022 May 31;13(1):3034. PMID: 35641493
- 4. Yiran Zhu, Bingluo Zhou, et al. "LncRNA LINC00942 promotes chemoresistance in gastric cancer by suppressing MSI2 degradation to enhancec‐MycmRNA stability." Clin Transl Med. 2022 Jan;12(1):e703. PMID: 35073459
- 5. Xuan Li, Kai-Bin Yang, et al. "CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression." Autophagy. 2021 Dec;17(12):4323-4340. PMID: 33977871
- 6. Hong Lin, Yuan Yan, et al. "IP 6-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion." Nat Commun. 2021 Apr 28;12(1):2461. PMID: 33911083
- 7. Kathryn M. Spitler, Shwetha K. Shetty, et al. "ANGPTL4 from adipose, but not liver, is responsible for regulating plasma triglyceride partitioning."bioRxiv. June 3, 2020.
- 8. Yanan Li, Chaorong Wang, et al. "Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy." Acta Pharmaceutica Sinica B.
- 9. Xiufang Xiong, Danrui Cui, et al. "Neddylation modification of ribosomal protein RPS27L or RPS27 by MDM2 or NEDP1 regulates cancer cell survival." FASEB J. 2020 Oct;34(10):13419-13429. PMID: 32779270
- 10. Zhang X, Shi S, et al. "Suramin and NF449 are IP5K inhibitors that disrupt IP6-mediated regulation of cullin RING ligase and sensitize cancer cells to MLN4924/pevonedistat." J Biol Chem. 2020;jbc.RA120.014375. PMID: 32493769
- 11. Yang PM, Hong YH, et al. "Progressive Rotavirus Infection Downregulates Redox-Sensitive Transcription Factor Nrf2 and Nrf2-Driven Transcription Units." Oxid Med Cell Longev. 2020 Apr 4;2020:7289120. PMID: 32322337
- 12. Yu Q, Hu Z, et al. "Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes." Neoplasia. 2020;22(4):179-191. PMID: 32145688
- 13. Shu J, Cui D, et al. "SCFβ-TrCP-mediated degradation of TOP2β promotes cancer cell survival in response to chemotherapeutic drugs targeting topoisomerase II." Oncogenesis. 2020;9(2):8. PMID: 32015321
- 14. Cui D, Xiong X, et al. "FBXW7 Confers Radiation Survival by Targeting p53 for Degradation." Cell Rep. 2020 Jan 14;30(2):497-509.e4. PMID: 31940492
- 15. Codilupi T, Taube D, et al. "CRL4 ubiquitin ligase stimulates Fanconi anemia pathway-induced single-stranded DNA-RPA signaling." BMC Cancer. 2019 Nov 5;19(1):1042. PMID: 31690264
- 16. Mukhopadhyay U, Chanda S, et al. "Bi-phasic regulation of RNA interference during Rotavirus infection by modulation of Argonaute2." Cell Microbiol. 2019 Aug 19:e13101. PMID: 31424151
- 17. Cui D, Dai X, et al. "The cross talk of two family members of β-TrCP in the regulation of cell autophagy and growth." Cell Death Differ. 2019 Aug 13. PMID: 31406304
- 18. Povedano JM, Liou J, et al. "Engineering Forward Genetics into Cultured Cancer Cells for Chemical Target Identification." Cell Chem Biol. 2019 Jul 9. pii: S2451-9456(19)30207-7. PMID: 31303577
- 19. Xu J, Shi Q, et al. "Metabolic enzyme PDK3 forms a positive feedback loop with transcription factor HSF1 to drive chemoresistance." Theranostics. 2019 May 9;9(10):2999-3013. PMID: 31244938
- 20. Mao H, Tang Z, et al. "Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1." Protein Cell. 2019 Mar 9. PMID: 30850948
- 21. Zhou Q, Li H, et al. "Inhibiting neddylation modification alters mitochondrial morphology and reprograms energy metabolism in cancer cells." JCI Insight. 2019 Feb 21;4(4). pii:121582. PMID: 30668548
- 22. Chen X, Cui D, et al. "AKT inhibitor MK-2206 sensitizes breast cancer cells to MLN4924, a first-in-class NEDD8-activating enzyme (NAE) inhibitor." Cell Cycle. 2018;17(16):2069-2079. PMID: 30198810
- 23. Tan S, Liu F, et al. "CSN6, a subunit of the COP9 signalosome, is involved in early response to iron deficiency in Oryza sativa." Sci Rep. 2016 May 3;6:25485. PMID: 27137867
- 24. Lan H, Tang Z, Jin H, Sun Y. "Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep." 2016 Apr 11;6:24218. PMID: 27063292
Physical Appearance | A solid |
Storage | Store at -20°C |
M.Wt | 443.53 |
Cas No. | 905579-51-3 |
Formula | C21H25N5O4S |
Solubility | ≥22.18 mg/mL in DMSO; insoluble in H2O; ≥42.2 mg/mL in EtOH |
Chemical Name | [(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate |
SDF | Download SDF |
Canonical SMILES | C1CC2=CC=CC=C2C1NC3=NC=NC4=C3C=CN4C5CC(C(C5)O)COS(=O)(=O)N |
运输条件 | 蓝冰运输或根据您的需求运输。 |
一般建议 | 不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。溶液形式一般不宜长期储存,请尽快用完。 |
激酶实验[1]: | |
体外E1活化的激酶实验 |
使用时间分辨荧光能量转移实验来测量NAE的体外活性。酶促反应体系包含50 μL 50 mM HEPES、pH 7.5、0.05% BSA、5 mM MgCl2、20 μM ATP、250 μM谷胱甘肽、10 nM Ubc12-GST、75 nM NEDD8-Flag和0.3 nM重组人NAE酶,在384孔板中24℃孵育90分钟,然后用25 μL终止/检测缓冲液终止反应,缓冲液含有0.1 M HEPES、pH 7.5、0.05% Tween20、20 mM EDTA、410 mM KF、0.53 nM Europium-Cryptate标记的Flag-M2特异性单克隆抗体和8.125 μg/mL的PHYCOLINK蓝色荧光蛋白(XL-APC)标记的GST特异性抗体。在24℃下孵育2小时后,使用时间分辨荧光法在LJL Analyst HT Multi-Mode仪器上读取平板。使用类似的实验方案来测量其他E1酶。 |
细胞实验: [1] | |
细胞系 |
HCT-116细胞 |
制备方法 |
溶解度有限,若配制更高浓度的溶液,一般步骤如下:请将试管置于37℃加热10分钟和/或将其置于超声波浴中震荡一段时间。原液于-20℃可放置数月。 |
反应条件 |
24 h |
实验结果 |
用MLN4924处理HCT-116细胞24小时,以剂量依赖性方式减少Ubc12-NEDD8硫酯和NEDD8-胞质结合物,IC50小于0.1 μM。MLN4924使已知CRL底物CDT1、p27和NRF2的丰度增加。在HCT-116细胞中,观察到的最突出的表型是破坏S期调节导致细胞死亡。到24小时,大多数的细胞含有≥4N的DNA含量。 |
动物实验: [1] | |
动物模型 |
HCT-116荷瘤小鼠 |
给药剂量 |
皮下注射每日一次(QD)或每日两次(BID) |
实验结果 |
30 mg/kg和60 mg/kg MLN4924每天一次显著抑制肿瘤生长。此外,MLN4924每天给药一次,治疗两天,然后停止五天,进行三个周期,显著抑制肿瘤生长。所有剂量和方案都具有良好耐受性,在治疗结束时所有剂量组的平均体重减轻小于10%。 |
注意事项 |
请于室内测试所有化合物的溶解度。虽然化合物的实际溶解度可能与其理论值略有不同,但仍处于实验系统误差的允许范围内。 |
References: 1. Soucy TA, Smith PG, Milhollen MA et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6. |
质量控制和MSDS
- 批次: