GSK-690693

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C21H27N7O3
Molecular Weight	425.4842
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCN1C(=NC2=C(N=CC(OC[C@H]3CCCNC3)=C12)C#CC(C)(C)O)C4=NON=C4N

InChI

InChIKey=KGPGFQWBCSZGEL-ZDUSSCGKSA-N

InChI=1S/C21H27N7O3/c1-4-28-18-15(30-12-13-6-5-9-23-10-13)11-24-14(7-8-21(2,3)29)16(18)25-20(28)17-19(22)27-31-26-17/h11,13,23,29H,4-6,9-10,12H2,1-3H3,(H2,22,27)/t13-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/18800763 | https://www.clinicaltrials.gov/ct2/show/NCT00666081http://adisinsight.springer.com/drugs/800026285
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/26698230 | https://www.ncbi.nlm.nih.gov/pubmed/18800763 | https://www.ncbi.nlm.nih.gov/pubmed/18381444

GSK690693 is an aminofurazan derivative, a novel ATP-competitive, low-nanomolar pan-Akt kinase inhibitor. It is selective for the Akt isoforms versus the majority of kinases in other families; however, it does inhibit additional members of the AGC kinase family. GlaxoSmithKline was developing this compound for the treatment of lymphoma solid tumours but the clinical development of this compound was terminated due to the associated side-effect of transient hyperglycemia.

CNS Activity

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/18800763	Inhibitor 8297	2.0 nM [IC50]
Serine/threonine-protein kinase AKT2 17 Target ID: CHEMBL2431 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18800763	Inhibitor 8297	13.0 nM [IC50]
Serine/threonine-protein kinase AKT3 17 Target ID: CHEMBL4816 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18800763	Inhibitor 8297	9.0 nM [IC50]
RAC-alpha serine/threonine-protein kinase 1 Target ID: P31749 Gene ID: 207.0 Gene Symbol: AKT1 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18800763	Inhibitor 8297	1.0 nM [Ki]
RAC-beta serine/threonine-protein kinase 2 Target ID: P31751 Gene ID: 208.0 Gene Symbol: AKT2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18800763	Inhibitor 8297	4.0 nM [Ki]
RAC-gamma serine/threonine-protein kinase 1 Target ID: Q9Y243 Gene ID: 10000.0 Gene Symbol: AKT3 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/18800763	Inhibitor 8297	13.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 592 Sources: http://adisinsight.springer.com/drugs/800026285	Primary		Phase I 428	Unknown Approved Use Unknown
Cancer 592 Sources: https://www.clinicaltrials.gov/ct2/show/NCT00666081	Primary		Phase I 428	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
		252160402
Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity.	2008 Apr 1	18381444
Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.	2008 Sep 25	18800763
AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines.	2009 Feb 19	19064730
Initial testing (stage 1) of the Akt inhibitor GSK690693 by the pediatric preclinical testing program.	2010 Dec 15	20740623
GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt.	2010 Jan 15	20075391
Personalized therapies in the cancer "omics" era.	2010 Jul 29	20670437
Causal reasoning identifies mechanisms of sensitivity for a novel AKT kinase inhibitor, GSK690693.	2010 Jul 6	20604938
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
Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells.	2012 Jul	22532600

Patents

Sample Use Guides

In Vivo Use Guide

Administered intravenously at a concentration between 0.1 - 4.8 mg/mL by slow infusion over 4 h.

Route of Administration: Intravenous

In Vitro Use Guide

Acute lymphoblastic leukemia cell lines were plated at optimal densities in 96-well plates and incubated overnight. Cells were then treated with DMSO or GSK 690693 (ranging from 30 uM-1.5 nM) for 72 hours. GSK 690693 was effective in inhibiting proliferation of cells from both T-cell and B-/pre-B–cell origin within the ALL cell panel, with 19 of the 20 T-ALL (95%) and 12 of the 15 B-ALL (80%) found to be sensitive to GSK 690693.

Name

Type

Language

GSK-690693

Common Name

English

GSK 690693

Code

English

(-)-4-(2-(4-AMINO-1,2,5-OXADIAZOL-3-YL)-1-ETHYL-7-((3S)-3-PIPERIDINYLMETHOXY)-1H-IMIDAZO(4,5-C)PYRIDIN-4-YL)-2-METHYL-3-BUTYN-2-OL

Systematic Name

English

3-BUTYN-2-OL, 4-(2-(4-AMINO-1,2,5-OXADIAZOL-3-YL)-1-ETHYL-7-((3S)-3-PIPERIDINYLMETHOXY)-1H-IMIDAZO(4,5-C)PYRIDIN-4-YL)-2-METHYL-

Systematic Name

English

4-(2-(4-AMINO-1,2,5-OXADIAZOL-3-YL)-1-ETHYL-7-((3S)-3-PIPERIDINYLMETHOXY)-1H-IMIDAZO(4,5-C)PYRIDIN-4-YL)-2-METHYL-3-BUTYN-2-OL, (-)-

Systematic Name

English

GSK690693

Code

English

Code System Code Type Description

CAS

937174-76-0