Pevonedistat

Summary

Pevonedistat (CHEMBL1231160) is a phase-3 clinical-stage small-molecule antineoplastic agent; indicated across 16 conditions including acute myeloid leukemia and myelodysplastic syndrome.

At a glance

• Status: Max clinical phase 3 (not approved)
• Modality: Small molecule
• Indications: 16 conditions
• Clinical trials: 41
• Chemistry: 443.5 Da · C21H25N5O4S

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL1231160
Name	Pevonedistat
Type	Small molecule
Max phase	3
FDA approved	no
PubChem CID	16720766
ChEBI	CHEBI:145535
Molecular formula	C21H25N5O4S
Molecular weight	443.5
InChIKey	MPUQHZXIXSTTDU-QXGSTGNESA-N

SMILES: C1CC2=CC=CC=C2[C@H]1NC3=C4C=CN(C4=NC=N3)[C@@H]5C[C@H]([C@H](C5)O)COS(=O)(=O)N

IUPAC 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

ChEBI definition: A pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine which is substituted by a (1S)-2,3-dihydro-1H-inden-1-ylnitrilo group at position 4 and by a (1S,3S,4S)-3-hydroxy-4-[(sulfamoyloxy)methyl]cyclopentyl group at position 7. It is a potent and selective NEDD8-activating enzyme inhibitor with an IC50 of 4.7 nM, and currently under clinical investigation for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes.

Pharmacological roles (ChEBI): apoptosis inducer, antineoplastic agent.

Also known as: MLN 4924, MLN-4924, MLN-4924003, MLN4924, Pevonedistat, PEVONEDISTAT, UNII-S3AZD8D215, PEVONEDISTAT (MLN4924), Pevanodistat, Pevonedistat hydrochloride

Parent form; salt/anhydrous children: CHEMBL2364622

Patent coverage: 633 distinct patent families (1,480 SureChEMBL compound mentions), from 3 matched compound structure(s). One matched structure accounts for 1,350 (91%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Broader ChEMBL bioactivity targets: 7 (assay-derived). Sample: NEDD8-activating enzyme E1 catalytic subunit, NEDD8-activating enzyme E1 regulatory subunit, SUMO-activating enzyme, Ubiquitin-like modifier-activating enzyme 6, NEDD8 activating enzyme, Ubiquitin-like protein NEDD8, Ubiquitin-like modifier-activating enzyme 1.

Bioactivity

ChEMBL activities: 13 potent at pChembl ≥ 5 of 13 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
NAE1	9.59	IC50	0.26	nM	CHEMBL_ACT_24863232
NAE1	8.4	IC50	4	nM	CHEMBL_ACT_24775876
NAE1	8.4	IC50	4	nM	CHEMBL_ACT_24863263
NAE1	8.4	IC50	4	nM	CHEMBL_ACT_25964117
NAE1	8.4	IC50	4	nM	CHEMBL_ACT_26165306
NEDD8	8.33	IC50	4.7	nM	CHEMBL_ACT_18483951
UBA3	8.3	IC50	5	nM	CHEMBL_ACT_18579282
NAE1	7.52	EC50	30	nM	CHEMBL_ACT_24863266
NAE1	6.75	IC50	180	nM	CHEMBL_ACT_22909535
Q02053	5.82	IC50	1500	nM	CHEMBL_ACT_24775878
UBA6	5.75	IC50	1800	nM	CHEMBL_ACT_24775879
NAE1	5.47	EC50	3400	nM	CHEMBL_ACT_18372590
SAE1	5.09	IC50	8200	nM	CHEMBL_ACT_24775877

Target pathways

No target-pathway data for this drug (no mapped target genes).

Indications & clinical

Indications

16 indications (0 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
acute myeloid leukemia	3	MONDO:0018874	EFO:0000222
myelodysplastic syndrome	2	MONDO:0018881	EFO:0000198
non-small cell lung carcinoma	2	MONDO:0005233	EFO:0003060
chronic myelomonocytic leukemia	2	MONDO:0020311	EFO:1001779
hepatocellular carcinoma	2	MONDO:0007256	EFO:0000182
cholangiocarcinoma	2	MONDO:0019087	EFO:0005221
metastatic melanoma	1	MONDO:0005191	EFO:0002617
acute lymphoblastic leukemia	1	MONDO:0004967	EFO:0000220
diffuse large B-cell lymphoma	1	MONDO:0018905	EFO:0000403
mesothelioma	1	MONDO:0005065	EFO:0000588
neoplasm	1	MONDO:0005070	EFO:0000616
plasma cell myeloma	1	MONDO:0009693	EFO:0001378
neoplasm of mature B-cells	1	MONDO:0004949	EFO:0000096
leukemia	1	MONDO:0005059	EFO:0000565
lymphoid neoplasm	1	MONDO:0005157	EFO:0001642

1 further indication record had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 41.

Phase distribution

Phase	Trials
PHASE1	22
PHASE2	10
PHASE1/PHASE2	6
PHASE3	2
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04090736	PHASE3	ACTIVE_NOT_RECRUITING	Study to Compare Azacitidine Plus Pevonedistat Versus Azacitidine in Patients With Acute Myeloid Leukemia Not Eligible for Standard Chemotherapy
NCT03268954	PHASE3	COMPLETED	Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine as First-Line Treatment for Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML), or Low-Blast Acute Myelogenous Leukemia (AML)
NCT03013998	PHASE1/PHASE2	RECRUITING	Study of Biomarker-Based Treatment of Acute Myeloid Leukemia
NCT03330821	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Pevonedistat, Cytarabine, and Idarubicin in Treating Patients With Acute Myeloid Leukemia
NCT03862157	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Azacitidine, Venetoclax, and Pevonedistat in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia
NCT03965689	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Combination of MLN4924 (Pevonedistat), Carboplatin, and Paclitaxel in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Who Have Previously Been Treated With Immunotherapy
NCT04175912	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Combination of Pevonedistat With Chemotherapy for Bile Duct Cancer of the Liver
NCT01415765	PHASE1/PHASE2	WITHDRAWN	MLN4924 Compared With MLN4924 Plus Chemotherapy for Large B-cell Lymphoma
NCT02610777	PHASE2	COMPLETED	An Efficacy and Safety Study of Pevonedistat Plus Azacitidine Versus Single-Agent Azacitidine in Participants With Higher-Risk Myelodysplastic Syndromes (HR MDS), Chronic Myelomonocytic Leukemia (CMML) and Low-Blast Acute Myelogenous Leukemia (AML)
NCT03228186	PHASE2	TERMINATED	Trial of Pevonedistat Plus Docetaxel in Patients With Previously Treated Advanced Non-Small Cell Lung Cancer
NCT03238248	PHASE2	COMPLETED	Pevonedistat and Azacitidine in MDS or MDS/MPN Patients Who Fail Primary Therapy With DNA Methyl Transferase Inhibitors
NCT03319537	PHASE1/PHASE2	TERMINATED	Pevonedistat Alone and in Combination With Chemotherapy in Patients With Mesothelioma
NCT03709576	PHASE2	TERMINATED	Pevonedistat and Azacitidine as Maintenance Therapy After Allogeneic Stem Cell Transplantation for Non-Remission AML
NCT03745352	PHASE2	WITHDRAWN	Pevonedistat With Azacitidine Versus Azacitidine Alone in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
NCT04266795	PHASE2	COMPLETED	A Study of Pevonedistat and Venetoclax Combined With Azacitidine to Treat Acute Myeloid Leukemia (AML) in Adults Unable to Receive Intensive Chemotherapy
NCT04712942	PHASE2	COMPLETED	Treatment of MDS/AML Patients With an Impending Hematological Relapse With AZA or ATA and Pevonedistat
NCT04800627	PHASE1/PHASE2	TERMINATED	Pevonedistat and Pembrolizumab for the Treatment of dMMR/MSI-H Metastatic or Locally Advanced Unresectable Solid Tumor
NCT04985656	PHASE2	WITHDRAWN	A Study of Pevonedistat Combined With Decitabine and Cedazuridine in Adults With Higher-risk Myelodysplastic Syndromes
NCT03479268	PHASE1	ACTIVE_NOT_RECRUITING	Pevonedistat and Ibrutinib in Treating Participants With Relapsed or Refractory CLL or Non-Hodgkin Lymphoma
NCT00677170	PHASE1	COMPLETED	Study of MLN4924 in Adult Patients With Nonhematologic Malignancies
NCT00722488	PHASE1	COMPLETED	Study of MLN4924, a Novel Inhibitor of Nedd8 Activating Enzyme, in Adult Patients With Lymphoma or Multiple Myeloma
NCT00911066	PHASE1	COMPLETED	MLN4924 for the Treatment of Acute Myelogenous Leukemia, Myelodysplastic Syndrome, and Acute Lymphoblastic Leukemia
NCT01011530	PHASE1	COMPLETED	Dose Escalation Study of MLN4924 in Adults With Melanoma
NCT01814826	PHASE1	COMPLETED	Study of MLN4924 Plus Azacitidine in Treatment-naive Participants With Acute Myelogenous Leukemia (AML) Who Are 60 Years or Older
NCT01862328	PHASE1	COMPLETED	Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Participants With Solid Tumors
NCT02122770	PHASE1	COMPLETED	Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Participants With Advanced Solid Tumors
NCT02782468	PHASE1	COMPLETED	A Study of Pevonedistat in Adult East Asian Participants
NCT03009240	PHASE1	COMPLETED	Pevonedistat and Decitabine in Treating Patients With High Risk Acute Myeloid Leukemia
NCT03057366	PHASE1	COMPLETED	A Study of [14 C]-Pevonedistat in Participants With Advanced Solid Tumors
NCT03323034	PHASE1	COMPLETED	Pevonedistat, Irinotecan, and Temozolomide in Treating Patients With Recurrent or Refractory Solid Tumors or Lymphoma
NCT03330106	PHASE1	COMPLETED	A Study to Evaluate the Effects of Pevonedistat on the Corrected QT (QTc) Interval in Participants With Advanced Solid Tumors
NCT03349281	PHASE1	COMPLETED	Pevonedistat With VXLD Chemotherapy for Adolescent/Young Adults With Relapsed/Refractory ALL or Lymphoblastic NHL
NCT03386214	PHASE1	TERMINATED	Pevonedistat in Combination With Ruxolitinib for Treatment of Patients With Myelofibrosis
NCT03459859	PHASE1	COMPLETED	Pevonedistat and Low Dose Cytarabine in Adult Patients With AML and MDS
NCT03486314	PHASE1	COMPLETED	A Study to Evaluate the Effects of Rifampin on Pharmacokinetics (PK) of Pevonedistat in Participants With Advanced Solid Tumors
NCT03770260	PHASE1	COMPLETED	Ixazomib and Pevonedistat in Treating Patients With Multiple Myeloma That Has Come Back or Does Not Respond to Treatment
NCT03772925	PHASE1	TERMINATED	Pevonedistat and Belinostat in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
NCT03813147	PHASE1	COMPLETED	Pevonedistat, Azacitidine, Fludarabine Phosphate, and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome
NCT03814005	PHASE1	COMPLETED	A Study of Pevonedistat in People With Blood Cancers or Solid Tumors With Kidney or Liver Problems
NCT04172844	PHASE1	TERMINATED	Pevonedistat, Azacitidine (or Decitabine), and Venetoclax for the Treatment of Patients With Acute Myelogenous Leukemia

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

No PharmGKB pharmacogenomic data curated for this drug.

Related molecules

Related molecules

No competitor molecules sharing a primary target (ChEMBL phase ≥2 or PubChem drug-class).