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

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

Description

AT7519M or AT7519, a small molecule inhibitor of cyclin-dependent kinases 1, 2, 4, 5, and 9, participated in phase II clinical trials in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). As a result, in CLL, some patients had tumor reductions, but the objective response rate (ORR) was low. In MCL, activity was noted with ORR of 27%. In addition, AT7519M was studied in patients with previously treated multiple myeloma, to understand whether the drug alone or in combination with bortezomib were effective treatments. Recent experiments also have shown that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. It is known, that MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Cyclin-dependent kinase 1 27	Inhibitor 8,504	210.0 nM [IC50]
Cyclin-dependent kinase 2 23	Inhibitor 8,504	47.0 nM [IC50]
Cyclin-dependent kinase 4 26	Inhibitor 8,504	100.0 nM [IC50]
Cyclin-dependent kinase 6 16	Inhibitor 8,504	13.0 nM [IC50]
Cyclin-dependent kinase 9 24	Inhibitor 8,504	10.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Chronic lymphocytic leukemia 59	Primary	Phase II 1,147	Unknown
Multiple myeloma 159	Primary	Phase II 1,147	Unknown
Mantle cell lymphoma 24	Primary	Phase II 1,147	Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
591 ng/mL	27 mg/m² single, intravenous		AT-7519 plasma	Homo sapiens
508.7 ng/mL	21 mg/m² 2 times / week multiple, intravenous	ONALESPIB	AT-7519 plasma	Homo sapiens
459.3 ng/mL	21 mg/m² single, intravenous	ONALESPIB	AT-7519 plasma	Homo sapiens
591 ng/mL	27 mg/m² single, intravenous		AT-7519 plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
2449 ng × h/mL	21 mg/m² 2 times / week multiple, intravenous	ONALESPIB	AT-7519 plasma	Homo sapiens
2300 ng × h/mL	21 mg/m² single, intravenous	ONALESPIB	AT-7519 plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
13.1 h	27 mg/m² single, intravenous		AT-7519 plasma	Homo sapiens
10.7 h	21 mg/m² 2 times / week multiple, intravenous	ONALESPIB	AT-7519 plasma	Homo sapiens
11.1 h	21 mg/m² single, intravenous	ONALESPIB	AT-7519 plasma	Homo sapiens
13.1 h	27 mg/m² single, intravenous		AT-7519 plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
32.4 mg/m2 4 times / 3 weeks multiple, intravenous MTD	unhealthy, ADULT	DLT: Fatigue, Febrile neutropenia...
27 mg/m2 4 times / 3 weeks multiple, intravenous RP2D	unhealthy, ADULT	DLT: Mucositis...

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AEs

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AE	Significance	Dose	Population
Fatigue	grade 3, 20% DLT	32.4 mg/m2 4 times / 3 weeks multiple, intravenous MTD	unhealthy, ADULT
Febrile neutropenia	grade 3, 20% DLT	32.4 mg/m2 4 times / 3 weeks multiple, intravenous MTD	unhealthy, ADULT
Hypokalemia	grade 3, 20% DLT	32.4 mg/m2 4 times / 3 weeks multiple, intravenous MTD	unhealthy, ADULT
Mucositis	grade 3, 20% DLT	32.4 mg/m2 4 times / 3 weeks multiple, intravenous MTD	unhealthy, ADULT
Mucositis	grade 3, 6.7% DLT	27 mg/m2 4 times / 3 weeks multiple, intravenous RP2D	unhealthy, ADULT

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Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 2,252	inhibitor 2,438	inhibitor 2,507

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 2,153 CYP2C19 2,057	BCRP 697 P-gp 2,052 MRP1 113

Drug as perpetrator

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Target	Modality	Activity
CYP1A2 2,333	inhibitor 4,027	weak [Inhibition 10 uM]
CYP2C19 2,141	inhibitor 4,027	weak [Inhibition 10 uM]
CYP2C9 2,497	inhibitor 4,027	weak [Inhibition 10 uM]
CYP2D6 2,546	inhibitor 4,027	weak [Inhibition 10 uM]
CYP3A4 2,633	inhibitor 4,027	weak [Inhibition 10 uM]

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Drug as victim

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Target	Modality	Activity
MRP1 113	substrate 4,014	no
BCRP 697	substrate 4,014	weak
P-gp 2,052	substrate 4,014	yes

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PubMed

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Title	Date	PubMed
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

Showing 1 to 4 of 4 entries

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Patents

Sample Use Guides

In Vivo Use Guide

A Phase II study of AT7519M, a CDK Inhibitor, in Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia. Dose: 27 mg/m2, IV injection, 1 hour infusion. Schedule: 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.

Show entries

Name

Type

Language

AT 7519

Preferred Name

English

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

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

Systematic Name

English

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Classification Tree

Code System

Code

Protein Kinase Inhibitor

NCI_THESAURUS

C2185

Antineoplastic Protein Inhibitor

NCI_THESAURUS

C129825

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Code System

Code

Type

Description

EPA CompTox

DTXSID30233420

PRIMARY

NCI_THESAURUS

C64761

PRIMARY

NCIT

DRUG BANK

DB08142

PRIMARY

FDA UNII

X1BF92PW9T

PRIMARY

CAS

844442-38-2

PRIMARY

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ACTIVE MOIETY


					X1BF92PW9T

AT-7519

SALT/SOLVATE (PARENT)


					Z239O75N33

AT-7519 MESYLATE

SMILES

InChI

CNS Activity

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Overview

OverviewOther

Drug as perpetrator​

Drug as victim

PubMed

Patents

Sample Use Guides

C_max

T_1/2

Drug as perpetrator