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MedKoo Cat#: 201924 | Name: Pevonedistat (MLN-4924)
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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Pevonedistat, also known as MLN-4924 and TAK-924, is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with potential antineoplastic activity. NAE inhibitor MLN4924 binds to and inhibits NAE, which may result in the inhibition of tumor cell proliferation and survival. NAE activates Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8), an ubiquitin-like (UBL) protein that modifies cellular targets in a pathway that is parallel to but distinct from the ubiquitin-proteasome pathway (UPP).

Chemical Structure

Pevonedistat (MLN-4924)
Pevonedistat (MLN-4924)
CAS#905579-51-3 (free base)

Theoretical Analysis

MedKoo Cat#: 201924

Name: Pevonedistat (MLN-4924)

CAS#: 905579-51-3 (free base)

Chemical Formula: C21H25N5O4S

Exact Mass: 443.1627

Molecular Weight: 443.52

Elemental Analysis: C, 56.87; H, 5.68; N, 15.79; O, 14.43; S, 7.23

Price and Availability

Size Price Availability Quantity
10mg USD 90.00 Ready to ship
25mg USD 150.00 Ready to ship
50mg USD 250.00 Ready to ship
100mg USD 450.00 Ready to ship
200mg USD 750.00 Ready to ship
500mg USD 1,650.00 Ready to ship
1g USD 2,950.00 2 Weeks
2g USD 5,250.00 2 Weeks
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Related CAS #
1160295-21-5 (HCl) 905579-51-3 (free base)
Synonym
TAK-924; TAK 924; TAK924; MLN4924; MLN 4924; BAY-73-4506; BAY 73-4506; BAY73-4506; Pevonedistat.
IUPAC/Chemical Name
((1S,2S,4R)-4-(4-(((S)-2,3-dihydro-1H-inden-1-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulfamate
InChi Key
MPUQHZXIXSTTDU-QXGSTGNESA-N
InChi Code
InChI=1S/C21H25N5O4S/c22-31(28,29)30-11-14-9-15(10-19(14)27)26-8-7-17-20(23-12-24-21(17)26)25-18-6-5-13-3-1-2-4-16(13)18/h1-4,7-8,12,14-15,18-19,27H,5-6,9-11H2,(H2,22,28,29)(H,23,24,25)/t14-,15+,18-,19-/m0/s1
SMILES Code
O=S(OC[C@H]1[C@@H](O)C[C@H](N2C=CC3=C(N[C@H]4CCC5=C4C=CC=C5)N=CN=C32)C1)(N)=O
Appearance
white solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not soluble in water.
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO.
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
In vivo administration of MLN4924 to mice bearing xenograft tumors of OCI-Ly10 and OCI-Ly19 resulted in a pharmacodynamic response of NAE pathway inhibition. In both models, a single dose of MLN4924 resulted in time and dose-dependent inhibition of total neddylated cullin levels and stabilization of CDL substrates including the CDL3Keap1 substrate, Nrf-2. Notably, in the OCI-Ly10 model, a single dose of MLN4924 resulted in a marked elevation of pIkBa levels, indicative of NF-kB pathway inhibition, and induction of apoptosis. In both OCI-Ly10 and OCI-Ly19 xenograft models, inhibition of the NAE pathway following repeated daily and intermittent dosing of MLN4924 translated into significant tumor growth inhibition. In the OCI-Ly10 model tumor regressions were observed showing this model to be particularly sensitive to MLN4924 treatment, reflecting the addiction of these tumors to NF-kB signaling. Additionally we demonstrate an inhibition of the NAE pathway and NF-KB signaling in a primary human tumor DLBCL xenograft model (PHTX-22L) resulting in tumor regressions following MLN4924 treatment. In summary, in tumors dependent on NF-kB signaling for growth and survival, MLN4924 inhibition of CDL activity provides a novel mechanism for targeted NF-kB pathway modulation and therapeutic intervention. In addition, these data demonstrate that MLN4924 is a novel agent that has broad activity in pre-clinical models of lymphoma. (source: Michael Milhollen, Usha Narayanan*, Allison J Berger, Michael Thomas, Tary Traore, Jie Yu, Julie Zhang, Erik Koenig, James J. Garnsey, Steven P. Langston, Teresa A Soucy, and Peter G Smith,  MLN4924, a Novel Small Molecule Inhibitor of Nedd8-Activating Enzyme, Demonstrates Potent Anti-Tumor Activity in Diffuse Large B-Cell Lymphom, 50th ASH Annual Meeting and Exposition, or see website: http://ash.confex.com/ash/2008/webprogram/Paper9916.html).       
Biological target:
MLN4924 is a small molecule inhibitor of Nedd8 activating enzyme (NAE) with IC50 of 4 nM.
In vitro activity:
Treatment of HCT-116 cells with MLN4924 for 24 h resulted in a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, with an IC50,0.1 mM (Fig. 3a), resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1 (refs 22-24), p27 (refs 14, 25) and NRF2 (also known as NFE2L2)26, but not non- CRL substrates (Supplementary Fig. 3). In similar experiments, the accumulation of other CRL substrates including c-Jun27, HIF1a (ref. 28), cyclin E29, CDC25A (ref. 30), EMI1 (also known as FBXO5)31 and phosphorylated IkBa (refs 13, 32) was observed (data not shown). The observed accumulation of CRL substrates in MLN4924- treated HCT-116 cells is consistent with the idea that the abundance of most, if not all, CRL target proteins can be modulated by NAE inhibition. HCT-116 cells were treated with 0.3 mM MLN4924, a concentration sufficient to decrease the steady-state level of NEDD8-cullin conjugates by.80% relative to untreated cells (Fig. 3a, dashed outline), and the cell-cycle profiles were monitored by DNA content using flow cytometry. As early as 8 h after compound treatment, cells began to accumulate in S-phase (Fig. 3b). By 24 h, a significant fraction of cells contained$4N DNA content (Fig. 3b, dashed outline); however, the absence of detectable phosphohistone H3 (pH3) staining indicated that the cells were not transitioning into mitosis (Fig. 3a). By 48 h, an increase in the sub-2N DNA content population was observed, consistent with cells undergoing apoptosis and further supported by the accumulation of cleaved caspase 3 and PARP (Fig. 3a). Reference: Nature. 2009 Apr 9;458(7239):732-6. https://doi.org/10.1038/nature07884
In vivo activity:
To assess the ability of MLN4924 to inhibit NAE in vivo, HCT-116 tumour-bearing mice received a single subcutaneous dose of 10, 30 or 60mgkg21 MLN4924, and tumours were excised at various timepoints over the subsequent 24 h period. The pharmacodynamic effects of treatment were assessed in tumour lysates which were analysed for NEDD8-cullin, NRF2 and CDT1 protein levels (Fig. 4a-c). A single dose of MLN4924 resulted in a dose- and time-dependent decrease of NEDD8-cullin levels as early as 30 min after administration of compound (Fig. 4a), with maximal effect 1-2 h post-dose. A significant difference was observed between the 10 and 60 mgkg21 response profiles (P,0.01), although the 10 and 30mgkg21 (P50.11) and 30 and 60 mg kg21 (P50.24) profiles were not significantly different from each other. A single dose of MLN4924 also led to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 (Fig. 4b, c). For all dose levels, NRF2 protein levels peaked 2-4 h after administration ofMLN4924 and started to decline by 4-8 h post-dose. The timing of CDT1 accumulation was slightly delayed compared to NRF2, peaking 4 h after MLN4924 administration (Fig. 4c). Evidence of DNA damage in the tumour was indicated by the increased levels of phosphorylated CHK1 (Ser 317) at 8 h after a single administration of 30 and 60 mgkg21 MLN4924 (Fig. 4d). It should be noted that MLN4924 also decreased NEDD8-cullin levels in normal mouse tissue as illustrated in mouse bone marrow cells (Supplementary Fig. 5). These data suggest that MLN4924-mediated inhibition of NAE in this in vivo tumour model results in pathway responses and cellular phenotypic effects compatible with those observed in cultured cells. Reference: Nature. 2009 Apr 9;458(7239):732-6. https://doi.org/10.1038/nature07884
Solvent mg/mL mM
Solubility
DMSO 20.0 45.10
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 443.52 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol:
In vitro protocol:
1. Milhollen MA, Traore T, Adams-Duffy J, Thomas MP, Berger AJ, Dang L, Dick LR, Garnsey JJ, Koenig E, Langston SP, Manfredi M, Narayanan U, Rolfe M, Staudt LM, Soucy TA, Yu J, Zhang J, Bolen JB, Smith PG. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood. 2010 Sep 2;116(9):1515-23. doi: 10.1182/blood-2010-03-272567. Epub 2010 Jun 4. PMID: 20525923. 2. 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. doi: 10.1038/nature07884. PMID: 19360080.
In vivo protocol:
1. Milhollen MA, Traore T, Adams-Duffy J, Thomas MP, Berger AJ, Dang L, Dick LR, Garnsey JJ, Koenig E, Langston SP, Manfredi M, Narayanan U, Rolfe M, Staudt LM, Soucy TA, Yu J, Zhang J, Bolen JB, Smith PG. MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood. 2010 Sep 2;116(9):1515-23. doi: 10.1182/blood-2010-03-272567. Epub 2010 Jun 4. PMID: 20525923. 2. 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. doi: 10.1038/nature07884. PMID: 19360080.
1: Foster JH, Reid JM, Minard C, Woodfield S, Denic KZ, Isikwei E, Voss SD, Nelson M, Liu X, Berg SL, Fox E, Weigel BJ. Phase 1 study of NEDD8 activating enzyme inhibitor pevonedistat in combination with chemotherapy in pediatric patients with recurrent or refractory solid tumors (ADVL1615). Eur J Cancer. 2024 Aug 2;209:114241. doi: 10.1016/j.ejca.2024.114241. Epub ahead of print. PMID: 39096851. 2: Tang H, Pang X, Li S, Tang L. The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway. Biomolecules. 2024 Jun 21;14(7):738. doi: 10.3390/biom14070738. PMID: 39062453; PMCID: PMC11274557. 3: Jiang Z, Li Z, Chen Y, Nie N, Liu X, Liu J, Shen Y. MLN4924 alleviates autoimmune myocarditis by promoting Act1 degradation and blocking Act1-mediated mRNA stability. Int Immunopharmacol. 2024 Sep 30;139:112716. doi: 10.1016/j.intimp.2024.112716. Epub 2024 Jul 21. PMID: 39038386. 4: Gil-Pitarch C, Serrano-Maciá M, Simon J, Mosca L, Conter C, Rejano-Gordillo CM, Zapata-Pavas LE, Peña-Sanfélix P, Azkargorta M, Rodríguez-Agudo R, Lachiondo-Ortega S, Mercado-Gómez M, Delgado TC, Porcelli M, Aurrekoetxea I, Sutherland JD, Barrio R, Xirodimas D, Aspichueta P, Elortza F, Martínez-Cruz LA, Nogueiras R, Iruzubieta P, Crespo J, Masson S, McCain MV, Reeves HL, Andrade RJ, Lucena MI, Mayor U, Goikoetxea-Usandizaga N, González-Recio I, Martínez-Chantar ML. Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway. Cell Rep Med. 2024 Jul 16;5(7):101653. doi: 10.1016/j.xcrm.2024.101653. PMID: 39019009; PMCID: PMC11293357. 5: Zhou Q, Yu H, Chen Y, Ren J, Lu Y, Sun Y. The CRL3KCTD10 ubiquitin ligase-USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11. Proc Natl Acad Sci U S A. 2024 Jul 9;121(28):e2320655121. doi: 10.1073/pnas.2320655121. Epub 2024 Jul 3. PMID: 38959043; PMCID: PMC11252818. 6: Yang G, Wang Y, Hu S, Chen J, Chen L, Miao H, Li N, Luo H, He Y, Qian Y, Miao C, Feng R. Inhibition of neddylation disturbs zygotic genome activation through histone modification change and leads to early development arrest in mouse embryos. Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167292. doi: 10.1016/j.bbadis.2024.167292. Epub 2024 Jun 11. PMID: 38871031. 7: Powell RT, Rinkenbaugh AL, Guo L, Cai S, Shao J, Zhou X, Zhang X, Jeter-Jones S, Fu C, Qi Y, Baameur Hancock F, White JB, Stephan C, Davies PJ, Moulder S, Symmans WF, Chang JT, Piwnica-Worms H. Targeting neddylation and sumoylation in chemoresistant triple negative breast cancer. NPJ Breast Cancer. 2024 May 27;10(1):37. doi: 10.1038/s41523-024-00644-4. PMID: 38802426; PMCID: PMC11130334. 8: Shen S, Radhakrishnan SK, Harrell JC, Puchalapalli M, Koblinski J, Clevenger C. The Human Intermediate Prolactin Receptor I-tail Contributes Breast Oncogenesis by Targeting Ras/MAPK Pathway. Endocrinology. 2024 Apr 29;165(6):bqae039. doi: 10.1210/endocr/bqae039. PMID: 38713636. 9: Chen KH, Sun JM, Lin L, Liu JW, Liu XY, Chen GD, Chen H, Chen ZY. The NEDD8 activating enzyme inhibitor MLN4924 mitigates doxorubicin-induced cardiotoxicity in mice. Free Radic Biol Med. 2024 Jul;219:127-140. doi: 10.1016/j.freeradbiomed.2024.04.221. Epub 2024 Apr 16. PMID: 38614228. 10: Murthy GSG, Saliba AN, Szabo A, Harrington A, Abedin S, Carlson K, Michaelis L, Runaas L, Baim A, Hinman A, Maldonado-Schmidt S, Venkatachalam A, Flatten KS, Peterson KL, Schneider PA, Litzow M, Kaufmann SH, Atallah E. A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia. Haematologica. 2024 Apr 4. doi: 10.3324/haematol.2024.285014. Epub ahead of print. PMID: 38572562. 11: Sendo S, Machado CRL, Boyle DL, Benschop RJ, Perumal NB, Choi E, Wang W, Firestein GS. Dysregulated NUB1 and Neddylation Enhances Rheumatoid Arthritis Fibroblast-Like Synoviocyte Inflammatory Responses. Arthritis Rheumatol. 2024 Aug;76(8):1252-1262. doi: 10.1002/art.42856. Epub 2024 Jun 5. PMID: 38566346. 12: Zhou C, Yang T, Chen H, Xu J, Liu J, Liu X, Ma S, Liu X. Prognostic value of different radiation-related cell death genes in patients with lung adenocarcinoma. Radiother Oncol. 2024 Jun;195:110259. doi: 10.1016/j.radonc.2024.110259. Epub 2024 Mar 26. PMID: 38548112. 13: Murali SK, McCormick JA, Fenton RA. Regulation of the water channel aquaporin-2 by cullin E3 ubiquitin ligases. Am J Physiol Renal Physiol. 2024 May 1;326(5):F814-F826. doi: 10.1152/ajprenal.00049.2024. Epub 2024 Mar 28. PMID: 38545647. 14: Ishikawa C, Mori N. Inhibitory effect of a neddylation blockade on HTLV-1-infected T cells via modulation of NF-κB, AP-1, and Akt signaling. Leuk Lymphoma. 2024 Jul;65(7):978-988. doi: 10.1080/10428194.2024.2328219. Epub 2024 Mar 15. PMID: 38489672. 15: Kong T, Gaudin N, Gordon K, Cox MJ, Zhou AW, Oh ST. A phase I trial of pevonedistat in combination with ruxolitinib for the treatment of myelofibrosis. Ther Adv Hematol. 2024 Mar 13;15:20406207241237607. doi: 10.1177/20406207241237607. PMID: 38481947; PMCID: PMC10935761. 16: Chen M, Liu Y, Zuo M, Zhang M, Wang Z, Li X, Yuan D, Xu H, Yu G, Li M. Integrated analysis reveals the regulatory mechanism of the neddylation inhibitor MLN4924 on the metabolic dysregulation in rabbit granulosa cells. BMC Genomics. 2024 Mar 6;25(1):254. doi: 10.1186/s12864-024-10118-3. PMID: 38448814; PMCID: PMC10916191. 17: Doncheva R, D'Huart E, Sobalak N, Vigneron J, Demoré B. Physicochemical stability of pevonedistat at 50, 100 and 200 µg/mL diluted in 0.9% sodium chloride and at 10 mg/mL in partially used vials. Eur J Hosp Pharm. 2024 Feb 26:ejhpharm-2023-003884. doi: 10.1136/ejhpharm-2023-003884. Epub ahead of print. PMID: 38408796. 18: Chen Z, Wang Z, Zhu C, Deng H, Chen X. Inhibiting neddylation with MLN4924 potentiates hypoxia-induced apoptosis of mouse type B spermatogonia GC-2 cells. Gene. 2024 Jan 30;893:147935. doi: 10.1016/j.gene.2023.147935. Epub 2023 Oct 29. PMID: 38381506. 19: Li Y, Shen S, Guo H, Li H, Zhang L, Zhang B, Yu XF, Wei W. Pharmacological inhibition of neddylation impairs long interspersed element 1 retrotransposition. Cell Rep. 2024 Feb 27;43(2):113749. doi: 10.1016/j.celrep.2024.113749. Epub 2024 Feb 7. PMID: 38329876. 20: Chiba M, Shimono J, Suto K, Ishio T, Endo T, Goto H, Hasegawa H, Maeda M, Teshima T, Yang Y, Nakagawa M. Whole-genome CRISPR screening identifies molecular mechanisms of PD-L1 expression in adult T-cell leukemia/lymphoma. Blood. 2024 Apr 4;143(14):1379-1390. doi: 10.1182/blood.2023021423. PMID: 38142436; PMCID: PMC11033594.
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