Details
Stereochemistry | ACHIRAL |
Molecular Formula | C16H17Cl2N5O2 |
Molecular Weight | 382.244 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
ClC1=CC=CC(Cl)=C1C(=O)NC2=CNN=C2C(=O)NC3CCNCC3
InChI
InChIKey=OVPNQJVDAFNBDN-UHFFFAOYSA-N
InChI=1S/C16H17Cl2N5O2/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/h1-3,8-9,19H,4-7H2,(H,20,23)(H,21,25)(H,22,24)
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26202950
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.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL308 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555 |
210.0 nM [IC50] | ||
Target ID: CHEMBL301 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555 |
47.0 nM [IC50] | ||
Target ID: CHEMBL331 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555 |
100.0 nM [IC50] | ||
Target ID: CHEMBL2508 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555 |
13.0 nM [IC50] | ||
Target ID: CHEMBL3116 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555 |
10.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
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 |
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
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
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 |
AT-7519 plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
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 |
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 |
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
Dose | Population | Adverse 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: 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: Page: p.2264 |
DLT: Fatigue, Febrile neutropenia... Dose limiting toxicities: Fatigue (grade 3, 20%) Sources: Page: p.2264Febrile neutropenia (grade 3, 20%) Hypokalemia (grade 3, 20%) Mucositis (grade 3, 20%) |
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: 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: Page: p.2264 |
DLT: Mucositis... Dose limiting toxicities: Mucositis (grade 3, 6.7%) Sources: Page: p.2264 |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Page: p.2264 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Other Inhibitor | Other Substrate | Other Inducer |
---|---|---|
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
weak [Inhibition 10 uM] | ||||
weak [Inhibition 10 uM] | ||||
weak [Inhibition 10 uM] | ||||
weak [Inhibition 10 uM] | ||||
weak [Inhibition 10 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
no | ||||
weak | ||||
yes |
PubMed
Title | Date | PubMed |
---|---|---|
Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. | 2009 Feb |
|
AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples. | 2010 Apr |
|
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 |
Sample Use Guides
In Vivo Use Guide
Sources: https://clinicaltrials.gov/ct2/show/NCT01652144
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555
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.
Name | Type | Language | ||
---|---|---|---|---|
|
Common Name | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Code | English | ||
|
Systematic Name | English | ||
|
Code | English | ||
|
Systematic Name | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
NCI_THESAURUS |
C2185
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
||
|
NCI_THESAURUS |
C129825
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
DTXSID30233420
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
C64761
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | NCIT | ||
|
DB08142
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
X1BF92PW9T
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
844442-38-2
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
CHEMBL445813
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
11338033
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
300000038547
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY | |||
|
91326
Created by
admin on Sat Dec 16 01:48:17 GMT 2023 , Edited by admin on Sat Dec 16 01:48:17 GMT 2023
|
PRIMARY |
ACTIVE MOIETY
SALT/SOLVATE (PARENT)