AT-7519

Investigational

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

Structure Search

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)

HIDE SMILES / InChI

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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27750483 | https://clinicaltrials.gov/ct2/show/NCT01627054https://www.ncbi.nlm.nih.gov/pubmed/19174555 | https://astx.com/research-development/clinical-pipeline/at7519-cdk-inhibitor-solid-tumors/

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

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Cyclin-dependent kinase 1 27 Target ID: CHEMBL308 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555	Inhibitor 8297	210.0 nM [IC50]
Cyclin-dependent kinase 2 22 Target ID: CHEMBL301 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555	Inhibitor 8297	47.0 nM [IC50]
Cyclin-dependent kinase 4 22 Target ID: CHEMBL331 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555	Inhibitor 8297	100.0 nM [IC50]
Cyclin-dependent kinase 6 12 Target ID: CHEMBL2508 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555	Inhibitor 8297	13.0 nM [IC50]
Cyclin-dependent kinase 9 19 Target ID: CHEMBL3116 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19174555	Inhibitor 8297	10.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Chronic lymphocytic leukemia 59 Sources: http://adisinsight.springer.com/drugs/800023173	Primary	Phase II 1132	Unknown Approved Use Unknown
Multiple myeloma 159 Sources: http://adisinsight.springer.com/drugs/800023173	Primary	Phase II 1132	Unknown Approved Use Unknown
Mantle cell lymphoma 24 Sources: http://adisinsight.springer.com/drugs/800023173	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

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	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

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	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

T_1/2

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	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

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: 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

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: 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

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1524 CYP2C19 1478	BCRP 561 P-gp 1537 MRP1 107

Drug as perpetrator

Target	Modality	Activity
CYP1A2 1692	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/18656911/	weak [Inhibition 10 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/18656911/	weak [Inhibition 10 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/18656911/	weak [Inhibition 10 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/18656911/	weak [Inhibition 10 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/18656911/	weak [Inhibition 10 uM]

Drug as victim

Target	Modality	Activity
MRP1 107	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/25986678/	no
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/31515284/	weak
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/31515284/	yes

PubMed

Title	Date	PubMed
		252160234
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	18656911
Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines.	2009 Feb	19174555
AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples.	2010 Apr	20354122
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	20101221
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010 Nov 24	21095574
Comprehensive analysis of kinase inhibitor selectivity.	2011 Oct 30	22037378
A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.	2014 Dec 9	25393368
Cyclin-Dependent Kinase Inhibitor AT7519 as a Potential Drug for MYCN-Dependent Neuroblastoma.	2015 Nov 15	26202950
The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome.	2017 Feb	27965411
Anticancer and radiosensitizing effects of the cyclin-dependent kinase inhibitors, AT7519 and SNS‑032, on cervical cancer.	2018 Aug	29901072
Inhibition of cyclin-dependent kinases by AT7519 is effective to overcome chemoresistance in colon and cervical cancer.	2019 Jun 4	30979499

Patents

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 `Sat Dec 16 01:48:17 GMT 2023` Edited by `admin` on `Sat Dec 16 01:48:17 GMT 2023`
Record UNII	X1BF92PW9T
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AT-7519

Common Name

English

1H-PYRAZOLE-3-CARBOXAMIDE, 4-((2,6-DICHLOROBENZOYL)AMINO)-N-4-PIPERIDINYL

Common Name

English

CDKI AT7519

Common Name

English

AT 7519

Code

English

4-(2,6-DICHLORO-BENZOYLAMINO)-1H-PYRAZOLE-3-CARBOXYLIC ACID PIPERIDIN-4-YLAMIDE

Systematic Name

English

AT7519

Code

English

4-(2,6-DICHLOROBENZOYLAMINO)-1H-PYRAZOLE-3-CARBOXYLIC ACID N-(PIPERIDIN-4-YL)AMIDE

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2185