AT-13148

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C17H16ClN3O
Molecular Weight	313.781
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

NC[C@@](O)(C1=CC=C(Cl)C=C1)C2=CC=C(C=C2)C3=CNN=C3

InChI

InChIKey=IIRWNGPLJQXWFJ-KRWDZBQOSA-N

InChI=1S/C17H16ClN3O/c18-16-7-5-15(6-8-16)17(22,11-19)14-3-1-12(2-4-14)13-9-20-21-10-13/h1-10,22H,11,19H2,(H,20,21)/t17-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C17H16ClN3O
Molecular Weight	313.781
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	1 / 1
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

AT13148, being developed by Astex Pharmaceuticals and its collaborators, is an orally active small molecule inhibitor of Rho activated kinases (ROCK) 1 and 2 and of protein kinase (PK) A and is currently in phase 1 clinical studies under Cancer Research UK’s Clinical Development Program (CDP). AT13148 is currently being tested in a phase 1 clinical trial in patients with advanced solid tumors.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
cAMP-dependent protein kinase (PKA) 18	Inhibitor 8,504	3.0 nM [IC50]
Rho-associated protein kinase 2 25	Inhibitor 8,504	4.0 nM [IC50]
Rho-associated protein kinase 1 20	Inhibitor 8,504	6.0 nM [IC50]
Ribosomal protein S6 kinase 1 4	Inhibitor 8,504	8.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Advanced solid cancer 30	Primary		Phase I 438	Unknown

C_max

Value	Dose	Analyte	Population
50 nM	20 mg 1 times / day multiple, oral	AT-13148 plasma	Homo sapiens
50 nM	20 mg 1 times / day multiple, oral	AT-13148 plasma	Homo sapiens
400 nM	180 mg single, oral	AT-13148 plasma	Homo sapiens
400 nM	160 mg single, oral	AT-13148 plasma	Homo sapiens
20 nM	5 mg single, oral	AT-13148 plasma	Homo sapiens
120 nM	40 mg single, oral	AT-13148 plasma	Homo sapiens
700 nM	300 mg single, oral	AT-13148 plasma	Homo sapiens

AUC

Value	Dose	Analyte	Population
20000 nM × h	180 mg single, oral	AT-13148 plasma	Homo sapiens
20000 nM × h	160 mg single, oral	AT-13148 plasma	Homo sapiens
900 nM × h	5 mg single, oral	AT-13148 plasma	Homo sapiens
2100 nM × h	40 mg single, oral	AT-13148 plasma	Homo sapiens
40000 nM × h	300 mg single, oral	AT-13148 plasma	Homo sapiens

T_1/2

Value	Dose	Analyte	Population
24 h	20 mg 1 times / day multiple, oral	AT-13148 plasma	Homo sapiens
24 h	20 mg 1 times / day multiple, oral	AT-13148 plasma	Homo sapiens
40 h	180 mg single, oral	AT-13148 plasma	Homo sapiens
40 h	160 mg single, oral	AT-13148 plasma	Homo sapiens
60 h	5 mg single, oral	AT-13148 plasma	Homo sapiens
15 h	40 mg single, oral	AT-13148 plasma	Homo sapiens
60 h	300 mg single, oral	AT-13148 plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
240 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76	DLT: Elevated liver enzymes...
240 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76	DLT: Pneumonitis...
300 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76	DLT: Hypotension, Hypotension... Other AEs: Hypotension...
180 mg 3 times / week multiple, oral MTD	unhealthy, 34–76	DLT: Maculopapular rash...

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AEs

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AE	Significance	Dose	Population
Elevated liver enzymes	16.7% DLT	240 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76
Pneumonitis	grade 3, 14.3% DLT	240 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76
Hypotension	grade 2, 40%	300 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76
Hypotension	grade 3, 20% DLT	300 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76
Hypotension	grade 4, 20% DLT	300 mg 3 times / week multiple, oral Highest studied dose	unhealthy, 34–76

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
1PlusChem LLC	1P008TU9	https://www.1pchem.com/search?query=1P008TU9
A2B Chem	AE11121	http://a2bchem.com/prod/AE11121
AChemBlock	M15888	http://www.achemblock.com/catalogsearch/result/?q=M15888
AK Scientific	2231AH	https://aksci.com/item_detail.php?cat=2231AH
Angene	AGN-PC-0WHA0C	http://www.angenechemical.com/productshow/AGN-PC-0WHA0C.html

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PubMed

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Title	Date	PubMed
Role of the anti-glioma drug AT13148 in the inhibition of Notch signaling pathway.	2015 Nov 15	26187072
AT13148, a first-in-class multi-AGC kinase inhibitor, potently inhibits gastric cancer cells both in vitro and in vivo.	2016 Sep 9	26828267

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Patents

Sample Use Guides

In Vivo Use Guide

Mice: 50 mg/kg p.o.

Route of Administration: Oral

In Vitro Use Guide

Screening of AT-13148 against a panel of kinases at 10 umol/L revealed >80% inhibition of the structurally related AGC kinases AKT, PKA, ROCK2, p70S6K, MSK, RSK1/2, and SGK

Substance Class	Chemical
Record UNII	A49037RP1E
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AT13148

Preferred Name

English

AT-13148

Common Name

English

BENZENEMETHANOL, .ALPHA.-(AMINOMETHYL)-.ALPHA.-(4-CHLOROPHENYL)-4-(1H-PYRAZOL-4-YL)-, (.ALPHA.S)-

Systematic Name

English

(S)-1-(4-(1H-PYRAZOL-4-YL)PHENYL)-2-AMINO-1-(4-CHLOROPHENYL)ETHANOL

Systematic Name

English

(+)-(S)-2-AMINO-1-(4-CHLOROPHENYL)-1-(4-(1H-PYRAZOL-4-YL)PHENYL)ETHANOL

Systematic Name

English

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Code System

Code

Type

Description

NCI_THESAURUS

C101786

PRIMARY

PUBCHEM

24905401

PRIMARY

SMS_ID

100000166972

PRIMARY

EVMPD

SUB181270

PRIMARY

ChEMBL

CHEMBL3544960

PRIMARY

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Related Record

Type

Details


					0JQ7O17JE9

RHO-ASSOCIATED PROTEIN KINASE 2

TARGET -> INHIBITOR

Interaction Type:

COMPETITIVE INHIBITOR

Qualification:

IC50

Amount:

RELATIONSHIP_AMOUNT 4 NANOMOLAR (average)


					DK566K8T76

RHO-ASSOCIATED PROTEIN KINASE 1

TARGET -> INHIBITOR

Interaction Type:

COMPETITIVE INHIBITOR

Amount:

RELATIONSHIP_AMOUNT 6 NANOMOLAR (average)

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Related Record

Type

Details


					A49037RP1E

AT-13148

ACTIVE MOIETY

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SMILES

InChI

Originator

Approval Year

Targets

Conditions

Cmax

AUC

T1/2

Doses

AEs

Sourcing

PubMed

Patents

Sample Use Guides

C_max

T_1/2