PEVONEDISTAT

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H25N5O4S
Molecular Weight	443.519
Optical Activity	UNSPECIFIED
Defined Stereocenters	4 / 4
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

NS(=O)(=O)OC[C@@H]1C[C@H](C[C@@H]1O)N2C=CC3=C(N[C@H]4CCC5=CC=CC=C45)N=CN=C23

InChI

InChIKey=MPUQHZXIXSTTDU-QXGSTGNESA-N

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

HIDE SMILES / InChI

Molecular Formula	C21H25N5O4S
Molecular Weight	443.519
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	4 / 4
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Pevonedistat (MLN4924), discovered by Millennium, is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. This drug is in phase II clinical trial for the treatment acute myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes. In addition in phase I for treatment acute lymphoblastic leukemia. The ability of MLN4924 to cross the blood-brain barrier, its low toxicity, and clinical efficacy in other cancers suggests that this drug is an attractive treatment against glioblastomas.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
NEDD8-activating enzyme E1 catalytic subunit 2	Substrate 661

Conditions

Condition	Modality	Highest Phase	Product
Acute lymphoblastic leukemia 27	Primary	Phase I 438	Unknown
Myelodysplastic syndromes 61	Primary	Phase II 1,147	Unknown
Acute myeloid leukemia 141	Primary	Phase II 1,147	Unknown
Leukemia, myelomonocytic, chronic 2	Primary	Phase II 1,147	Unknown

C_max

Value	Dose	Analyte	Population
1173 ng/mL	78 mg/m² 3 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
648 ng/mL	59 mg/m² 3 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
1212 ng/mL	83 mg/m² 2 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
2452 ng/mL	157 mg/m² 1 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
3591 ng/mL	209 mg/m² 2 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
3857 ng × h/mL	78 mg/m² 3 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
2506 ng × h/mL	59 mg/m² 3 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
3869 ng × h/mL	83 mg/m² 2 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
8932 ng × h/mL	157 mg/m² 1 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
12300 ng × h/mL	209 mg/m² 2 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
12 h	83 mg/m² 2 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
10.1 h	157 mg/m² 1 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens
10.4 h	209 mg/m² 2 times / week multiple, intravenous	PEVONEDISTAT plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
278 mg/m2 2 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT	Disc. AE: Blood creatinine increased, Blood bilirubin increased...
209 mg/m2 2 times / week multiple, intravenous MTD	unhealthy, ADULT	DLT: Aspartate aminotransferase increased, Brain natriuretic peptide increased... Disc. AE: Acute renal failure, Acute hepatic failure...
59 mg/m2 3 times / week multiple, intravenous MTD	unhealthy, ADULT
83 mg/m2 2 times / week multiple, intravenous MTD	unhealthy, ADULT
147 mg/m2 2 times / week multiple, intravenous Studied dose	unhealthy, ADULT	Disc. AE: Multi-organ failure, Heart failure...

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AEs

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AE	Significance	Dose	Population
Blood bilirubin increased	grade 3, 50% Disc. AE	278 mg/m2 2 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT
Blood creatinine increased	grade 3, 50% Disc. AE	278 mg/m2 2 times / week multiple, intravenous Highest studied dose	unhealthy, ADULT
Aspartate aminotransferase increased	grade 1, 9% DLT, Disc. AE	209 mg/m2 2 times / week multiple, intravenous MTD	unhealthy, ADULT
Brain natriuretic peptide increased	grade 1, 9% DLT, Disc. AE	209 mg/m2 2 times / week multiple, intravenous MTD	unhealthy, ADULT
Acute hepatic failure	grade 4, 9% Disc. AE	209 mg/m2 2 times / week multiple, intravenous MTD	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1,946 inhibitor 2,252	inhibitor 2,438	inhibitor 2,507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1,741	P-gp 2,052 BCRP 697

Drug as perpetrator

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Target	Modality	Activity
P-gp 1,932	inhibitor 4,027	inconclusive [IC50 9.2 uM]
CYP3A4 2,633	inhibitor 4,027	no
CYP2C9 2,497	inhibitor 4,027	yes [IC50 21.3174 uM]
CYP2D6 2,546	inhibitor 4,027	yes [IC50 8.4866 uM]

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Drug as victim

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Target	Modality	Activity	Clinical evidence
CYP3A4 1,946	substrate 4,014	major	yes (co-administration study)
BCRP 697	substrate 4,014	yes
P-gp 2,052	substrate 4,014	yes

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
001 Chemical	DY110895	https://www.001chemical.com/chem/search?q=DY110895
1PlusChem LLC	1P008TYZ	https://www.1pchem.com/search?query=1P008TYZ
1PlusChem LLC	1P00GUL4	https://www.1pchem.com/search?query=1P00GUL4
AK Scientific	2557AH	https://aksci.com/item_detail.php?cat=2557AH
AK Scientific	3866AH	https://aksci.com/item_detail.php?cat=3866AH

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PubMed

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Title	Date	PubMed
An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer.	2009 Apr 9	19360080
Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer.	2009 Jun 15	19509147
Biochemical and cellular effects of inhibiting Nedd8 conjugation.	2010 Jul 30	20603103
Rictor Undergoes Glycogen Synthase Kinase 3 (GSK3)-dependent, FBXW7-mediated Ubiquitination and Proteasomal Degradation.	2015 May 29	25897075

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Patents

Sample Use Guides

In Vivo Use Guide

Azacitidine 75 mg/m^2, intravenously or subcutaneously, on Days 1 to 5, Days 8 and 9 and pevonedistat 20 mg/m^2, 60-minute (±10) infusion, intravenously, on Days 1, 3, and 5 in 28-day treatment cycles.

Route of Administration: Intravenous

In Vitro Use Guide

Unknown

Substance Class	Chemical
Record UNII	S3AZD8D215
Record Status	`Validated (UNII)`
Record Version

Show entries

Name

Type

Language

pevonedistat [INN]

Preferred Name

English

PEVONEDISTAT

Official Name

English

SULFAMIC ACID, ((1S,2S,4R)-4-(4-(((1S)-2,3-DIHYDRO-1H-INDEN-1-YL)AMINO)-7H-PYRROLO(2,3-D)PYRIMIDIN-7-YL)-2-HYDROXYCYCLOPENTYL)METHYL ESTER

Common Name

English

((1S,2S,4R)-4-(4-(((1S)-2,3-DIHYDRO-1H-INDEN-1-YL)AMINO(-7H-PYRROLO(2,3-D)PYRIMIDIN-7-YL)-2-HYDROXYCYCLOPENTYL)METHYL SULFAMATE

Common Name

English

MLN4924

Code

English

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Classification Tree

Code System

Code

Designated

FDA ORPHAN DRUG

331310

Positive

EU-Orphan Drug

EU/3/18/2120

Designated

FDA ORPHAN DRUG

331510

Pharmacologic Substance

NCI_THESAURUS

C471

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Code System

Code

Type

Description

FDA UNII

S3AZD8D215

PRIMARY

USAN

YY-149

PRIMARY

CAS

905579-51-3

PRIMARY

EPA CompTox

DTXSID701022549

PRIMARY

EVMPD

SUB179279

PRIMARY

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Related Record

Type

Details


					28I8PCX76B

PEVONEDISTAT HYDROCHLORIDE

SALT/SOLVATE -> PARENT

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Related Record

Type

Details


					S3AZD8D215

PEVONEDISTAT

ACTIVE MOIETY

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SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator