AKT inhibitor VIII

Names

[ Name ]:
AKT inhibitor VIII

[Synonym ]:
2H-Benzimidazol-2-one, 1,3-dihydro-1-[1-[[4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl]methyl]-4-piperidinyl]-
Akti-1/2
1,3-Dihydro-1-(1-((4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one
1-{1-[4-(7-phenyl-1H-imidazo[4,5-g]quinoxalin-6-yl)benzyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one
Akt inhibitor VIII
1-{1-[4-(6-Phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)benzyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one
imidazoquinoxaline 16h
Akt Inhibitor VIII,Isozyme-Selective,Akti-1/2

Biological Activity

[Description]:

AKT inhibitor VIII is a cell-permeable quinoxaline compound that has been shown to potently, selectively, allosterically, and reversibly inhibit Akt1, Akt2, and Akt3 activity with IC50s of 58 nM, 210 nM, and 2119 nM, respectively.

[Related Catalog]:

Signaling Pathways >> PI3K/Akt/mTOR >> Akt

Research Areas >> Cancer

[Target]

Akt1:58 nM (IC50)

Akt2:210 nM (IC50)

Akt3:2119 nM (IC50)

[In Vitro]

When LnCaP cells are pretreated with AKT inhibitor VIII and then incubated with TRAIL, a dramatic increase in caspase-3 activity (6-10-fold relative to control or TRAIL alone) is observed. This sensitization of tumor cell lines with AKT inhibitor VIII is not limited to LnCaP cells as similar apoptosis induction is observed in HT29, MCF7, and A2780 cells, among others, with chemosensitizers such as camptothecin, herceptin, and doxorubicin[1]. The furanodiene-induced decrease of p-Akt and Akt expressions is enhanced by the Akt inhibitor VIII pretreatment. Furthermore, the furanodiene-induced PARP cleavage is enhanced by Akt inhibitor VIII pretreatment. The Akt inhibitor VIII shows no effect on cleaved PARP expression but decreases the p-Akt and Akt expressions[2]. AKT inhibitor VIII decreases cell viability and increases phosphatidylserine (PS) translocation to the outer leaflet of the plasma membrane, DNA fragmentation, Caspase-9 cleavage, Caspase-3 activation and PARP proteolysis in hESC lines WA01 (H1) and WA09 (H9) and in a hiPSCs cell line generated in our laboratory (FN2.1)[3].

[In Vivo]

Mice are dosed with AKT inhibitor VIII (50 mpk, 3 doses, ip, every 90 min) achieving plasma concentrations of 1.5-2.0 μM, and then the animals are tail vein injected with IGF to stimulate Akt phosphorylation. By IP Western, both basal and IGF stimulated Akt1 and Akt2 phosphorylation are inhibited in mouse lung, with no effect on Akt3 phosphorylation[1].

[Cell Assay]

PSC are plated onto Matrigel coated 96-well plates at densities between 1×103-3×105 cells per well and grown until confluence. 24 hours post-treatments, 50 μg/well of activated 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5 [(phenylamino) carbonyl]-2 H-tetrazolium hydroxide(XTT) in PBS containing 0.3 μg/well of N-methyl dibenzopyrazine methyl sulfate (PMS) are added (final volume 100 μL) and incubated for 1-2 hours at 37°C. Cellular metabolic activity is determined spectrophotometrically at 450 nm.

[References]

[1]. Lindsley, et al. Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors. Bioorg. Med. Chem. Lett. (2005), 15(3), 761-764.

[2]. Zhong Z, et al. Furanodiene, a Natural Product, Inhibits Breast Cancer Growth Both in vitro and in vivo. Cell Physiol Biochem. 2012;30(3):778-90. Epub 2012 Aug 2.

[3]. Leonardo Romorini, et al. AKT/GSK3β signaling pathway is critically involved in human pluripotent stem cell survival. Sci Rep. 2016; 6: 35660

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Melting Point ]:
242-245ºC (dec.)

[ Molecular Formula ]:
C₃₄H₂₉N₇O

[ Molecular Weight ]:
551.640

[ Exact Mass ]:
551.243347

[ PSA ]:
95.49000

[ LogP ]:
5.10

[ Index of Refraction ]:
1.734

AKT inhibitor VIII

Names

Biological Activity

Chemical & Physical Properties

Related Compounds