Molecular Weight (MW)

480.52

Formula

C23H28N8O4

CAS No.

1032568-63-0 (free base);

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: <1 mg/mL

Water:<1 mg/mL

Ethanol: <1 mg/mL

Solubility (In vivo)

10% Trifluoroacetic acid water solution: 1mg/mL

Other info

Chemical Name: 2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)pyrimidine-5-carboxamide

InChi Key: PZBCKZWLPGJMAO-UHFFFAOYSA-N

InChi Code: InChI=1S/C23H28N8O4/c1-33-19-17(35-10-2-6-30-8-11-34-12-9-30)4-3-16-18(19)28-23(31-7-5-25-20(16)31)29-21(32)15-13-26-22(24)27-14-15/h3-4,13-14H,2,5-12H2,1H3,(H2,24,26,27)(H,28,29,32)

SMILES Code: O=C(C1=CN=C(N)N=C1)NC2=NC3=C(C=CC(OCCCN4CCOCC4)=C3OC)C5=NCCN25.

Synonyms

Aliqopa; BAY 80-6946; BAY80-6946; BAY-80-6946; BAY806946; BAY-806946; BAY 806946;

In Vitro

In vitro: In both KPL4 cells and LPA-stimulated PC3 cells, BAY 80-6946 reduces pAKT levels. In a subset of human cancer cell lines with PIK3CA mutations and/or overexpression of HER2, BAY 80-6946 shows antiproliferative activity and induces apoptosis. The combination of HER2-targeted therapies and BAY 80-6946 inhibits growth more effectively than either therapy used alone, and can restore sensitivity to trastuzumab and lapatinib in cells.

Kinase Assay: The effect of BAY 80-6946 on PI3Kα, PI3Kβ, and PI3Kγ activity is measured by the inhibition of 33P incorporation into phosphatidylinositol (PI) in 384-well MaxiSorp(R) plates coated with 2 μg/well of PI and phosphatidylserine (PS) (1:1 molar ratio). In each PI3K isoform assay, 9 μL of reaction buffer (50 mM MOPSO, pH 7.0, 100 mM NaCl, 4 mM MgCl2, 0.1% BSA) containing 7.5 ng of His-tagged N-terminal truncated p110α or p110β protein, or 25 ng of purified human p110γ protein, is used. The reaction is started by adding 5 μL of a 40-μM ATP solution containing 20 μCi/mL [33>/sup>P]-ATP. After 2 hours incubation at room temperature, the reaction is terminated by addition of 5 μL of a 25-mM EDTA solution. The plates are washed and Ultima Gold(TM) scintillation cocktail (25 μL) is then added. The radioactivity incorporated into the immobilized PI substrate is determined with a BetaPlate Liquid Scintillation Counter.

Cell Assay: Cell proliferation over a 72-hour period is determined using the CellTiter-Glo(R) luminescent cell viability kit. Briefly, cells are plated in separate microtiter plates. Following an overnight incubation at 37oC, luminescence values in the t=0 hour plates are determined. Test compounds diluted in growth medium are added to the t=72 hour plates, and the cells are then incubated for 72 hours at 37oC. Luminescence values are determined with a Wallac 1420 Victor2(TM) 1420 multilabel HTS counter after a 10-minute reaction with CellTiter-Glo(R) solution. The percentage inhibition of cell growth is calculated by subtracting the luminescence values in the t=0 hour plates from the corresponding values in the t=72 hour plates. Differences in values between drug-treated cells and controls are used to determine the percentage inhibition of cell growth.

In Vivo

In rat KPL4 or HCT116 tumor xenograft model, BAY 80-6946 (6 mg/kg, i.v.) induces 100% complete tumor regression. In nude mice with Lu7860 erlotinib-resistant, patient-derived NSCLC and MAXF1398 patient-derived luminal breast tumor models, BAY 80-6946 (14 mg/kg, i.v.) also causes tumor growth inhibition.

Animal model

Rats bearing KPL4 or HCT116 xenografts

Formulation & Dosage

Formulated in PEG400/acidified water (0.1 N HCl, pH 3.5; 20/80, v/v) or 5% mannitol; 6 mg/kg; i.v.

References

Mol Cancer Ther. 2013 Nov;12(11):2319-30; Breast Cancer Res Treat. 2015 Jan;149(2):373-83.

Activity of BAY 80-6946 in xenograft models using an every second day (Q2D) schedule. Mol Cancer Ther. 2013, 12(11), 2319-2330.

Activity of BAY 80-6946 in xenograft models using a twice a day (BID) once-weekly schedule.

Antiproliferative IC50 values of BAY 80-6946 in cancer cell lines from various indications with gene mutation status