A-674563

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H22N4O
Molecular Weight	358.4363
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=NNC2=C1C=C(C=C2)C3=CC(OC[C@@H](N)CC4=CC=CC=C4)=CN=C3

InChI

InChIKey=BPNUQXPIQBZCMR-IBGZPJMESA-N

InChI=1S/C22H22N4O/c1-15-21-11-17(7-8-22(21)26-25-15)18-10-20(13-24-12-18)27-14-19(23)9-16-5-3-2-4-6-16/h2-8,10-13,19H,9,14,23H2,1H3,(H,25,26)/t19-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956255 | https://www.ncbi.nlm.nih.gov/pubmed/26920060
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/26970307

A-674563 is a potent, orally available Akt1 inhibitor with an IC50 value of 11nM. Also displays activity against PKA and CDK2 with IC50 values of 16nM and 46nM respectively. A-674563 dose-dependently inhibited survival and proliferation of U937 AML cells and six lines of human AML progenitor cells, yet sparing human peripheral blood mononuclear leukocytes (PBMCs). A-674563 activated caspase-3/9 and apoptosis in the AML cells. intraperitoneal injection of A-674563 at well-tolerated doses suppressed U937 leukemic xenograft tumor growth in nude mice, whiling significantly improving the animal survival. A-674563 exerts potent anti-leukemic activity in vitro and in vivo, possibly via concurrent targeting Akt and SphK1 signalings. A-674563 also exerts potent anti-melanoma activity, involving Akt-dependent and Akt-independent mechanisms.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Serine/threonine-protein kinase AKT 29 Target ID: CHEMBL4282 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956255	Inhibitor 8297	11.0 nM [Ki]
cAMP-dependent protein kinase (PKA) 18 Target ID: CHEMBL2094138 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956255	Inhibitor 8297	16.0 nM [Ki]
Cyclin-dependent kinase 2 22 Target ID: CHEMBL301 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15956255	Inhibitor 8297	46.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute myeloid leukemia 136 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26920060	Primary		Preclinical	Unknown Approved Use Unknown
Melanoma 88 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26970307	Primary		Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
AKT crystal structure and AKT-specific inhibitors.	2005 Nov 14	16288296
Concurrent targeting Akt and sphingosine kinase 1 by A-674563 in acute myeloid leukemia cells.	2016 Apr 15	26920060

Patents

Sample Use Guides

In Vivo Use Guide

Mice: In vivo, A-674563 (25 - 100 mg/kg, lavage daily) oral gavage inhibited A375 xenograft growth in severe combined immunodeficiency (scid) mice.

Route of Administration: Oral

In Vitro Use Guide

A-674563 at 10-1000 nM significantly inhibited A375 cell proliferation

Name

Type

Language

A-674563

Common Name

English

(.ALPHA.S)-.ALPHA.-(((5-(3-METHYL-1H-INDAZOL-5-YL)-3-PYRIDINYL)OXY)METHYL)BENZENEETHANAMINE

Systematic Name

English

A674563

Code

English

5-(5-((2S)-2-AMINO-3-PHENYLPROPOXY)PYRIDIN-3-YL)-3-METHYL-1H-INDAZOLE

Systematic Name

English

BENZENEETHANAMINE, .ALPHA.-(((5-(3-METHYL-1H-INDAZOL-5-YL)-3-PYRIDINYL)OXY)METHYL)-, (.ALPHA.S)-

Systematic Name

English

Code System Code Type Description

EPA CompTox

DTXSID10462115