Pevonedistat (MLN-4924)
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MedKoo CAT#: 201924

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

Description: 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

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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: 443.16273
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
10.0mg USD 150.0 Ready to ship
25.0mg USD 250.0 Ready to ship
50.0mg USD 550.0 Ready to ship
100.0mg USD 850.0 Ready to ship
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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

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

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 20.0 45.1

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
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.

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1. Brownell, James E.; Sintchak, Michael D.; Gavin, James M.; Liao, Hua; Bruzzese, Frank J.; Bump, Nancy J.; Soucy, Teresa A.; Milhollen, Michael A.; Yang, Xiaofeng; Burkhardt, Anne L.; Ma, Jingya; Loke, Huay-Keng; Lingaraj, Trupti; Wu, Dongyun; Hamman, Kristin B.; Spelman, James J.; Cullis, Courtney A.; Langston, Steven P.; Vyskocil, Stepan; Sells, Todd B.; Mallender, William D.; Visiers, Irache; Li, Ping; Claiborne, Christopher F.; Rolfe, Mark; Bolen, Joseph B.; Dick, Lawrence R. Substrate-assisted inhibition of ubiquitin-like protein-activating enzymes: the NEDD8 E1 inhibitor MLN4924 forms a NEDD8-AMP mimetic in situ. Molecular Cell (2010), 37(1), 102-111. 

2. Soucy, Teresa A.; Smith, Peter G.; Milhollen, Michael A.; Berger, Allison J.; Gavin, James M.; Adhikari, Sharmila; Brownell, James E.; Burke, Kristine E.; Cardin, David P.; Critchley, Stephen; Cullis, Courtney A.; Doucette, Amanda; Garnsey, James J.; Gaulin, Jeffrey L.; Gershman, Rachel E.; Lublinsky, Anna R.; McDonald, Alice; Mizutani, Hirotake; Narayanan, Usha; Olhava, Edward J.; Peluso, Stephane; Rezaei, Mansoureh; Sintchak, Michael D.; Talreja, Tina; Thomas, Michael P.; Traore, Tary; Vyskocil, Stepan; Weatherhead, Gabriel S.; Yu, Jie; Zhang, Julie; Dick, Lawrence R.; Claiborne, Christopher F.; Rolfe, Mark; Bolen, Joseph B.; Langston, Steven P. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature (London, United Kingdom) (2009), 458(7239), 732-736.

3. Langston, Steven P.; Olhava, Edward J.; Vyskocil, Stepan. Preparation of purine nucleoside derivatives as antitumor agents and inhibitors of E1 activating enzymes. PCT Int. Appl. (2007), 174 pp. CODEN: PIXXD2 WO 2007092213

4. Critchley, Stephen; Gant, Thomas G.; Langston, Steven P.; Olhava, Edward J.; Peluso, Stephane. Preparation of nucleoside derivatives as inhibitors of E1 activating enzymes. PCT Int. Appl. (2006), 214pp. CODEN: PIXXD2 WO 2006084281 .



Additional Information

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).