Name: MLN4924
Price: 292.00 USD

- Overview
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    Background
    
    MLN4924 is a potent and selective inhibitor of NEDD8-activating enzyme (NAE) with IC50 value of 4nM [1].
    MLN4924 binds NAE within the nucleotide-binding site competing with AMP. It is a potent inhibitor of NAE and is selective relative to the closely related enzymes UAE, SAE, UBA6 and ATG7 with IC50 values of 1.5, 8.2, 1.8 and 10μM, respectively. MLN4924 shows no effect to other ATP-using enzymes. In HCT-116 cells, MLN4924 treatment results in a decrease of Ubc12–NEDD8 thioester and NEDD8–cullin conjugates, thus resulting in an inhibition of protein degradation mediated by CRL-ubiquitinylation. CDT1 is one of these proteins. The accumulation of CDT1 can cause cell-cycle defects. In mice bearing HCT-116 xenografts, administrations of MLN4924 at 30mg/kg and 60mg/kg significantly inhibit the tumor growth and these doses are well tolerated. The anti-tumour activity of MLN4924 is also found both in mice bearing H522 lung tumour xenografts and in mice bearing Calu-6 lung carcinoma xenografts [1].
    
    [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.
- Properties
  - Alternative 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
    
    CAS Number
    
    905579-51-3
    
    Molecular Formula
    
    C21H25N5O4S
    
    Molecular Weight
    
    443.53
    
    Appearance
    
    A solid
    
    Purity
    
    98.00%
    
    Solubility
    
    ≥22.18 mg/mL in DMSO; insoluble in H2O; ≥42.2 mg/mL in EtOH
    
    Storage
    
    Store at -20°C
    
    * For Research Use Only
- Reference
  - 1. 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
    2. 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
    3. 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
    4. 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
    5. 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.
    6. 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
    7. 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
    8. 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
    9. 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
    10. 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
    11. 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
    12. 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
    13. 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
    14. 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
    15. 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
    16. 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
    17. Mao H, Tang Z, et al. "Neddylation inhibitor MLN4924 suppresses cilia formation by modulating AKT1." Protein Cell. 2019 Mar 9. PMID: 30850948
    18. 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
    19. 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
    20. 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
    21. 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

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