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Details

Stereochemistry ACHIRAL
Molecular Formula C16H17Cl2N5O2.CH4O3S
Molecular Weight 478.35
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of AT-7519 MESYLATE

SMILES

CS(O)(=O)=O.ClC1=CC=CC(Cl)=C1C(=O)NC2=CNN=C2C(=O)NC3CCNCC3

InChI

InChIKey=UELIMKCXGLIYCY-UHFFFAOYSA-N
InChI=1S/C16H17Cl2N5O2.CH4O3S/c17-10-2-1-3-11(18)13(10)15(24)22-12-8-20-23-14(12)16(25)21-9-4-6-19-7-5-9;1-5(2,3)4/h1-3,8-9,19H,4-7H2,(H,20,23)(H,21,25)(H,22,24);1H3,(H,2,3,4)

HIDE SMILES / InChI
Molecular Formula CH4O3S
Molecular Weight 96.106
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE
Molecular Formula C16H17Cl2N5O2
Molecular Weight 382.244
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry No
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

AT7519 is an inhibitor of Cyclin-dependent kinases (CDK). AT7519 potently inhibited CDK1,CDK2,CDK4 to CDK6, and CDK9. The compound had lower potency against other CDKs tested (CDK3 and CDK7) and was inactive against all of the non-CDK kinases tested with the exception of GSK3beta. AT7519 showed potent antiproliferative activity in a panel of human tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models. AT7519 is currently being investigated in Phase 1/2 studies.

CNS Activity

CNS Penetrant
2554
Curator's Comment: Preclinical studies in female NMRI homozygous (nu/nu) mice with neuroblastoma patient-derived MYCN-amplified AMC711T xenografts revealed dose-dependent growth inhibition, which correlated with intratumoral AT7519 levels. No human data available.

Originator

Approval Year

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 210.0 nM [IC50]
Inhibitor
8297
 47.0 nM [IC50]
Inhibitor
8297
 100.0 nM [IC50]
Inhibitor
8297
 13.0 nM [IC50]
Inhibitor
8297
 10.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
459.3 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/33095286
21 mg/m² single, intravenous
dose: 21 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered: ONALESPIB
ONALESPIB
 AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
508.7 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/33095286
21 mg/m² 2 times / week multiple, intravenous
dose: 21 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered: ONALESPIB
ONALESPIB
 AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
591 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/25393368
27 mg/m² single, intravenous
dose: 27 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered:
AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
2300 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/33095286
21 mg/m² single, intravenous
dose: 21 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered: ONALESPIB
ONALESPIB
 AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
2449 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/33095286
21 mg/m² 2 times / week multiple, intravenous
dose: 21 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered: ONALESPIB
ONALESPIB
 AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
11.1 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/33095286
21 mg/m² single, intravenous
dose: 21 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered: ONALESPIB
ONALESPIB
 AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
10.7 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/33095286
21 mg/m² 2 times / week multiple, intravenous
dose: 21 mg/m²
route of administration: Intravenous
experiment type: MULTIPLE
co-administered: ONALESPIB
ONALESPIB
 AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
13.1 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/25393368
27 mg/m² single, intravenous
dose: 27 mg/m²
route of administration: Intravenous
experiment type: SINGLE
co-administered:
AT-7519 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
32.4 mg/m2 4 times / 3 weeks multiple, intravenous
MTD
Dose: 32.4 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 32.4 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
DLT: Fatigue, Febrile neutropenia...
Dose limiting toxicities:
Fatigue (grade 3, 20%)
Febrile neutropenia (grade 3, 20%)
Hypokalemia (grade 3, 20%)
Mucositis (grade 3, 20%)
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
27 mg/m2 4 times / 3 weeks multiple, intravenous
RP2D
Dose: 27 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 27 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 15
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 15
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
DLT: Mucositis...
Dose limiting toxicities:
Mucositis (grade 3, 6.7%)
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
AEs

AEs

AESignificanceDosePopulation
Fatigue grade 3, 20%
DLT
32.4 mg/m2 4 times / 3 weeks multiple, intravenous
MTD
Dose: 32.4 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 32.4 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
Febrile neutropenia grade 3, 20%
DLT
32.4 mg/m2 4 times / 3 weeks multiple, intravenous
MTD
Dose: 32.4 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 32.4 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
Hypokalemia grade 3, 20%
DLT
32.4 mg/m2 4 times / 3 weeks multiple, intravenous
MTD
Dose: 32.4 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 32.4 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
Mucositis grade 3, 20%
DLT
32.4 mg/m2 4 times / 3 weeks multiple, intravenous
MTD
Dose: 32.4 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 32.4 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 5
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 5
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
Mucositis grade 3, 6.7%
DLT
27 mg/m2 4 times / 3 weeks multiple, intravenous
RP2D
Dose: 27 mg/m2, 4 times / 3 weeks
Route: intravenous
Route: multiple
Dose: 27 mg/m2, 4 times / 3 weeks
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
unhealthy, ADULT
n = 15
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 15
Sources:
https://pubmed.ncbi.nlm.nih.gov/25393368
Page: p.2264
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
inhibitor
1587
inhibitor
1767
inhibitor
1852

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP1A2
1524

CYP2C19
1478
BCRP
561

P-gp
1537

MRP1
107
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
CYP1A2
1692
 weak [Inhibition 10 uM]
CYP2C19
1553
 weak [Inhibition 10 uM]
CYP2C9
1819
 weak [Inhibition 10 uM]
CYP2D6
1891
 weak [Inhibition 10 uM]
CYP3A4
1925
 weak [Inhibition 10 uM]
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
MRP1
107
 no
BCRP
561
 weak
P-gp
1537
 yes
PubMed

PubMed

TitleDatePubMed
Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.
2008 Aug 28
Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines.
2009 Feb
AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition.
2010 Apr 22
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.
2010 Nov 24
Comprehensive analysis of kinase inhibitor selectivity.
2011 Oct 30
A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.
2014 Dec 9
Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.
2015 Nov 15
The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome.
2017 Feb
Anticancer and radiosensitizing effects of the cyclin-dependent kinase inhibitors, AT7519 and SNS‑032, on cervical cancer.
2018 Aug
Inhibition of cyclin-dependent kinases by AT7519 is effective to overcome chemoresistance in colon and cervical cancer.
2019 Jun 4
Patents

Patents

07385059
3
07745638
3
07825140
2
08013163
2
08080666
2
08293767
2
08404718
3
08779147
3
20060194843
2
JP2006528163A
5
JP4681548B2
3

Sample Use Guides

In Vivo Use Guide
AT7519M: 27 mg/m2 IV injection, 1 hour infusion, 27 mg/m2/day twice weekly x 2 weeks every 3 weeks (days 1, 4, 8 and 11)
Route of Administration: Intravenous
In Vitro Use Guide
AT7519 showed potent antiproliferative activity (40-940 nmol/L) in a panel of human tumor cell lines, and the mechanism of action was shown here to be consistent with the inhibition of CDK1 and CDK2 in solid tumor cell lines. AT7519 caused cell cycle arrest followed by apoptosis in human tumor cells and inhibited tumor growth in human tumor xenograft models.
Substance Class Chemical
Created
by admin
on Fri Dec 15 15:48:20 UTC 2023
Edited
by admin
on Fri Dec 15 15:48:20 UTC 2023
Record UNII
Z239O75N33
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
AT-7519 MESYLATE
Common Name English
AT-7519M
Common Name English
AT7519M
Code English
1H-PYRAZOLE-3-CARBOXAMIDE, 4-((2,6-DICHLOROBENZOYL)AMINO)-N-4-PIPERIDINYL-, METHANESULPHONATE (1:1)
Systematic Name English
4-((2,6-DICHLOROBENZOYL)AMINO)-N-PIPERIDIN-4-YL-1H-PYRAZOLE-3-CARBOXAMIDE METHANESULFONATE
Systematic Name English
AT 7519M [WHO-DD]
Common Name English
4-((2,6-DICHLOROBENZOYL)AMINO)-1H-PYRAZOLE-3-CARBOXIC ACIDE PIPERIDIN-4-YLAMIDE MESILATE SALT
Common Name English
Code System Code Type Description
PUBCHEM
23657720
Created by admin on Fri Dec 15 15:48:20 UTC 2023 , Edited by admin on Fri Dec 15 15:48:20 UTC 2023
PRIMARY
FDA UNII
Z239O75N33
Created by admin on Fri Dec 15 15:48:20 UTC 2023 , Edited by admin on Fri Dec 15 15:48:20 UTC 2023
PRIMARY
SMS_ID
100000175617
Created by admin on Fri Dec 15 15:48:20 UTC 2023 , Edited by admin on Fri Dec 15 15:48:20 UTC 2023
PRIMARY
CAS
902135-89-1
Created by admin on Fri Dec 15 15:48:20 UTC 2023 , Edited by admin on Fri Dec 15 15:48:20 UTC 2023
PRIMARY
Related Record Type Details
Structure of AT-7519
PARENT -> SALT/SOLVATE
Related Record Type Details
Structure of AT-7519
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