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[CAS NO. 1160295-21-5] Pevonedistat hydrochloride

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Catalog:	HY-10484
Brand:	MCE
CAS:	1160295-21-5

Overview

MDL	MFCD17215201
Molecular Weight	479.98
Molecular Formula	C21H26ClN5O4S
SMILES	O=S(OC[C@H]1[C@H](C[C@@H](C1)N2C=CC3=C(N=CN=C32)N[C@H]4CCC5=C4C=CC=C5)O)(N)=O.Cl

For research use only. We do not sell to patients.

93 Publications Citing Use of MCE

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[93]Harvard Medical School LINCS LIBRARY

Summary

Pevonedistat hydrochloride (MLN4924 hydrochloride) is a potent and selective NEDD8-activating enzyme (NAE) inhibitor, with an IC ₅₀ of 4.7 nM ^[1] .

IC50 & Target

IC50: 4.7 nM (NAE) ^[1]

In Vitro

Pevonedistat (MLN4924) is a potent inhibitor of NAE (half-maximal inhibitory concentration (IC ₅₀ =0.004 μM), and is selective relative to the closely related enzymes UAE, SAE, UBA6 and ATG7 (IC ₅₀ =1.5, 8.2, 1.8 and >10 μM, respectively). Pevonedistat (MLN4924) treatment inhibits overall protein turnover in cultured HCT-116 cells. Treatment of HCT-116 cells with Pevonedistat (MLN4924) for 24 h results in a dose-dependent decrease of Ubc12-NEDD8 thioester and NEDD8-cullin conjugates, with an IC ₅₀ < 0.1 μM, resulting in a reciprocal increase in the abundance of the known CRL substrates CDT1, p27 and NRF2 (also known as NFE2L2), but not non-CRL substrates ^[1] . Pevonedistat induces CLL cell apoptosis and circumvented stroma-mediated resistance. Pevonedistat promotes induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins ^[2] . Pevonedistat (MLN4924) rapidly inhibits cullin 1 neddylation and remarkably suppressed growth and survival as well as migration in a dose-and time-dependent manner in gastric cancer cells, and significantly suppresses migration by transcriptionally activating E-cadherin and repressing MMP-9 ^[3] .

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

In Vivo

Pevonedistat (MLN492410, 30 or 60 mg/kg, s.c.) leads to a dose- and time-dependent increase in the steady state levels of NRF2 and CDT1 in HCT-116 tumour-bearing mice, and decreases NEDD8-cullin levels in normal mouse tissue as illustrated in mouse bone marrow cells. Pevonedistat (MLN4924) administered on a BID schedule at 30 and 60 mg/kg inhibits tumour growth with T/C values of 0.36 and 0.15, respectively ^[1] .

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Clinical Trial

NCT Number	Sponsor	Condition	Start Date	Phase
NCT03965689	National Cancer Institute (NCI)	Metastatic Lung Non-Small Cell Squamous Carcinoma\|Metastatic Lung Non-Squamous Non-Small Cell Carcinoma\|Stage IIIB Lung Cancer AJCC v8\|Stage IV Lung Cancer AJCC v8\|Stage IVA Lung Cancer AJCC v8\|Stage IVB Lung Cancer AJCC v8\|Unresectable Lung Non-Small Cell Carcinoma\|Unresectable Lung Non-Squamous Non-Small Cell Carcinoma	September 3, 2019	Phase 2
NCT02122770	Millennium Pharmaceuticals, Inc.\|Takeda	Advanced Solid Tumors	April 1, 2014	Phase 1
NCT00911066	Millennium Pharmaceuticals, Inc.	Acute Myelogenous Leukemia\|Acute Lymphoblastic Leukemia\|Myelodysplastic Syndrome	June 2009	Phase 1
NCT03009240	City of Hope Medical Center\|National Cancer Institute (NCI)	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	August 21, 2017	Phase 1
NCT01814826	Millennium Pharmaceuticals, Inc.\|Takeda	Acute Myelogenous Leukemia	April 10, 2013	Phase 1
NCT04172844	Medical College of Wisconsin	Acute Myelogenous Leukemia	January 13, 2020	Phase 1
NCT03745352	National Cancer Institute (NCI)	Recurrent Acute Myeloid Leukemia\|Refractory Acute Myeloid Leukemia	May 20, 2019	Phase 2
NCT03319537	Memorial Sloan Kettering Cancer Center\|M.D. Anderson Cancer Center	Mesothelioma	October 5, 2017	Phase 1\|Phase 2
NCT03268954	Takeda\|Takeda Development Center Americas, Inc.	Myelodysplastic Syndrome\|Leukemia, Myelomonocytic, Chronic\|Leukemia, Myeloid, Acute	November 28, 2017	Phase 3
NCT03772925	National Cancer Institute (NCI)	Recurrent Acute Myeloid Leukemia\|Recurrent Myelodysplastic Syndrome\|Refractory Acute Myeloid Leukemia\|Refractory Myelodysplastic Syndrome	February 28, 2019	Phase 1
NCT03349281	Julio Barredo, MD\|Takeda\|University of Miami	Refractory Acute Lymphoblastic Leukemia\|Relapsed Acute Lymphoblastic Leukemia	March 25, 2019	Phase 1
NCT03386214	Washington University School of Medicine\|Takeda	Myelofibroses	April 23, 2018	Phase 1
NCT04090736	PETHEMA Foundation\|Millennium Pharmaceuticals, Inc.\|Dynamic Science S.L.	Leukemia, Myeloid, Acute	September 24, 2019	Phase 3
NCT01415765	National Cancer Institute (NCI)\|National Institutes of Health Clinical Center (CC)	Lymphoma, Diffuse Large-Cell B-cell\|Diffuse, Large B-cell Lymphoma\|Lymphoma, Diffuse Large-Cell\|Large-Cell Lymphoma, Diffuse	July 15, 2011	Phase 1\|Phase 2
NCT04985656	Takeda	Myelodysplastic Syndromes (MDS)	October 1, 2021	Phase 2
NCT04175912	National Cancer Institute (NCI)	Metastatic Cholangiocarcinoma\|Metastatic Hepatocellular Carcinoma\|Stage III Hepatocellular Carcinoma AJCC v8\|Stage III Intrahepatic Cholangiocarcinoma AJCC v8\|Stage IIIA Hepatocellular Carcinoma AJCC v8\|Stage IIIA Intrahepatic Cholangiocarcinoma AJCC v8\|Stage IIIB Hepatocellular Carcinoma AJCC v8\|Stage IIIB Intrahepatic Cholangiocarcinoma AJCC v8\|Stage IV Hepatocellular Carcinoma AJCC v8\|Stage IV Intrahepatic Cholangiocarcinoma AJCC v8\|Stage IVA Hepatocellular Carcinoma AJCC v8\|Stage IVB Hepatocellular Carcinoma AJCC v8\|Unresectable Cholangiocarcinoma\|Unresectable Hepatocellular Carcinoma\|Unresectable Intrahepatic Cholangiocarcinoma	January 31, 2020	Phase 2
NCT03228186	University of Michigan Rogel Cancer Center	Non-small Cell Lung Cancer	March 5, 2018	Phase 2
NCT01862328	Millennium Pharmaceuticals, Inc.\|Takeda	Solid Tumors	June 10, 2013	Phase 1
NCT01011530	Millennium Pharmaceuticals, Inc.	Metastatic Melanoma	December 2009	Phase 1
NCT03057366	Millennium Pharmaceuticals, Inc.\|Takeda	Advanced Solid Tumors, Neoplasms, Advanced Solid	May 11, 2017	Phase 1
NCT04484363	Takeda	Myelodysplastic Syndromes
NCT03862157	M.D. Anderson Cancer Center\|National Cancer Institute (NCI)	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	February 27, 2019	Phase 1\|Phase 2
NCT02782468	Millennium Pharmaceuticals, Inc.\|Takeda	Leukemia, Myeloid, Acute\|Myelodysplastic Syndromes	May 16, 2016	Phase 1
NCT03709576	Milton S. Hershey Medical Center\|Millennium Pharmaceuticals, Inc.\|Takeda	Acute Myeloid Leukemia (AML)	July 18, 2018	Phase 2
NCT02610777	Millennium Pharmaceuticals, Inc.\|Takeda	Myelodysplastic Syndromes\|Leukemia, Myelomonocytic, Chronic\|Leukemia, Myeloid, Acute	April 14, 2016	Phase 2
NCT03814005	Takeda	Myelodysplastic Syndromes\|Leukemia, Myelomonocytic, Chronic\|Leukemia, Myeloid, Acute\|Renal Insufficiency\|Liver Disease\|Neoplasms	July 10, 2019	Phase 1
NCT04712942	University of Leipzig\|Millennium Pharmaceuticals, Inc.	Acute Myeloid Leukemia in Remission\|Myelodysplastic Syndromes\|Minimal Residual Disease	January 1, 2021	Phase 2
NCT03330106	Millennium Pharmaceuticals, Inc.\|Takeda	Advanced Solid Neoplasm	November 15, 2017	Phase 1
NCT03013998	Beat AML, LLC	Previously Untreated Acute Myeloid Leukemia	November 2016	Phase 1\|Phase 2
NCT03486314	Millennium Pharmaceuticals, Inc.\|Takeda	Advanced Solid Neoplasm	August 13, 2018	Phase 1
NCT04266795	Takeda	Acute Myeloid Leukemia (AML)	October 13, 2020	Phase 2
NCT00722488	Millennium Pharmaceuticals, Inc.	Hematologic Malignancies\|Multiple Myeloma\|Lymphoma\|Hodgkin Lymphoma	June 2008	Phase 1
NCT03459859	Justin Watts, MD\|Takeda\|University of Miami	Acute Myelogenous Leukemia\|AML\|Advanced Myelodysplastic Syndromes\|MDS	May 21, 2018	Phase 1
NCT00677170	Millennium Pharmaceuticals, Inc.	Advanced Nonhematologic Malignancies	April 2008	Phase 1
NCT03323034	Children´s Oncology Group\|National Cancer Institute (NCI)	Recurrent Lymphoma\|Recurrent Malignant Solid Neoplasm\|Recurrent Primary Central Nervous System Neoplasm\|Refractory Lymphoma\|Refractory Malignant Solid Neoplasm\|Refractory Primary Central Nervous System Neoplasm	November 13, 2017	Phase 1
NCT03479268	City of Hope Medical Center\|National Cancer Institute (NCI)	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	March 22, 2018	Phase 1
NCT03813147	National Cancer Institute (NCI)\|Children´s Oncology Group	Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome\|Recurrent Acute Myeloid Leukemia\|Recurrent Myelodysplastic Syndrome\|Refractory Acute Myeloid Leukemia\|Refractory Myelodysplastic Syndrome	May 1, 2019	Phase 1
NCT03238248	Vanderbilt-Ingram Cancer Center\|National Cancer Institute (NCI)	Myelodysplastic Syndromes\|Myeloproliferative Neoplasm	August 7, 2017	Phase 2
NCT04800627	M.D. Anderson Cancer Center	Locally Advanced Malignant Solid Neoplasm\|Metastatic Malignant Solid Neoplasm\|Unresectable Malignant Solid Neoplasm	March 29, 2021	Phase 1\|Phase 2
NCT03770260	National Cancer Institute (NCI)	Recurrent Plasma Cell Myeloma\|Refractory Plasma Cell Myeloma	April 23, 2019	Phase 1
NCT03330821	University of Southern California\|National Cancer Institute (NCI)	Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome\|Acute Myeloid Leukemia With Myelodysplasia-Related Changes\|Therapy-Related Acute Myeloid Leukemia	April 18, 2018	Phase 1\|Phase 2

Appearance

Solid

Shipping

Room temperature in continental US; may vary elsewhere.

Storage

4°C, sealed storage, away from moisture

* In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

Solvent & Solubility

In Vitro:

DMSO : 100 mg/mL ( 208.34 mM ; Need ultrasonic)

H ₂ O : 10 mg/mL ( 20.83 mM ; Need ultrasonic)

Preparing
Stock Solutions

Concentration Solvent Mass	1 mg	5 mg	10 mg

1 mM	2.0834 mL	10.4171 mL	20.8342 mL
5 mM	0.4167 mL	2.0834 mL	4.1668 mL
10 mM	0.2083 mL	1.0417 mL	2.0834 mL

* Please refer to the solubility information to select the appropriate solvent.

In Vivo:

1.

Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline

Solubility: ≥ 2.5 mg/mL (5.21 mM); Clear solution
2.

Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline)

Solubility: ≥ 2.5 mg/mL (5.21 mM); Clear solution
3.

Add each solvent one by one: 10% DMSO >> 90% corn oil

Solubility: ≥ 2.5 mg/mL (5.21 mM); Clear solution

* All of the co-solvents are available by MCE.

References

[1] Soucy TA, et al. An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature. 2009 Apr 9;458(7239):732-6.
[2] J. Claire Godbersen, e tal. The Nedd8-Activating Enzyme Inhibitor MLN4924 Thwarts Microenvironment-Driven NF-κB Activation and Induces Apoptosis in Chronic Lymphocytic Leukemia B Cells.
[3] Lan H, et al. Neddylation inhibitor MLN4924 suppresses growth and migration of human gastric cancer cells. Sci Rep. 2016 Apr 11;6:24218.

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