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
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)
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 |
---|---|---|
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 |
|
The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome. | 2017 Feb |
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.
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23657720
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Z239O75N33
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100000175617
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902135-89-1
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ACTIVE MOIETY
SUBSTANCE RECORD