Molecular Weight (MW)

432.52

Formula

C27H24N6

CAS No.

1313881-70-7 (free base);

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 86 mg/mL (183.4 mM)

Water: <1 mg/mL

Ethanol: 6 mg/mL (12.8 mM)

SMILES

NC1=NC=CC=C1C2=NC3=CC=C(C4=CC=CC=C4)N=C3N2C5=CC=C(C6(N)CCC6)C=C5

Synonyms

ARQ092; ARQ-092; ARQ 092; 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine

In Vitro

In vitro activity: ARQ 092 blocks membrane translocation of inactive AKT and even dephosphorylates the membrane-associated active form, thereby perturbing AKT activity. Treatment with 50-500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. In a large panel of diverse cancer cell lines, ARQ 092 inhibits proliferation across multiple tumor types but are most potent in leukemia, breast, endometrial, and colorectal cancer cell lines. Moreover, inhibition by ARQ 092 is more prevalent in cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. ARQ 092 targets the PI3K/AKT pathway and AKT specifically and reduces phosphorylation of GSK3α and GSK3β in mutation-positive cells.

Kinase Assay: Miransertib (ARQ-092) is an orally bioavailable, selective, and potent allosteric Akt inhibitor with IC50s of 2.7 nM, 14 nM and 8.1 nM for Akt1, Akt2, Akt3, respectively.

Cell Assay: Cells (MDA-MB-453: 1.5×106; NCI-H1650: 1×106; KU-19-19: 0.7×106) are plated into 6 well plates, left overnight, and then treated with full media containing different concentrations (0, 0.012, 0.037, 0.11, 0.33, and 1 μM) of AKT inhibitors (ARQ 092, ARQ 751, MK-2206, GDC-0068) for 2 hours. Cells are treated under designated conditions and lysates are extracted. Proteins are resolved from extracts using SDS-PAGE followed by immunoblotting.

In Vivo

Short-term oral administration of ARQ 092 or hydroxyurea, a main therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with TNF-α. ARQ 092 is well tolerated at a continuous daily dose of 60 mg or a dose of 600 mg when administered once a week, for several months. ARQ 092 is likely to inhibit the activity of all AKT isoforms in intravascular cells and thereby attenuates the process of thrombosis and inflammation in SCD patients. ARQ 092 is highly active in a subset of endometrial tumors that harbor PI3K pathway gene mutations.

Animal model

Male SCD mice

Formulation & Dosage

Dissolved in Phosphoric acid (0.01 M); 100 mg/10ml/kg; Oral administration

References

PLoS One. 2015 Oct 15;10(10):e0140479; Haematologica. 2017 Feb;102(2):246-259; Sci Rep. 2015 Dec 11;5:17162.