Molecular Weight (MW)

469.54

Formula

C22H31N9O3

CAS No.

1620576-64-8

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 93 mg/mL (198.1 mM)

Water: <1 mg/mL

Ethanol: <1 mg/mL

Other Info

IUPAC/Chemical Name: 1-(4-(5-(5-amino-6-(5-(tert-butyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one
InChi Key: ZGRDYKFVDCFJCZ-UHFFFAOYSA-N
InChi Code: InChI=1S/C22H31N9O3/c1-5-31-19(26-18(29-31)13-6-9-30(10-7-13)15(33)8-11-32)14-12-24-17(23)16(25-14)20-27-28-21(34-20)22(2,3)4/h12-13,32H,5-11H2,1-4H3,(H2,23,24)
SMILES Code: O=C(N1CCC(C2=NN(CC)C(C3=NC(C4=NN=C(C(C)(C)C)O4)=C(N)N=C3)=N2)CC1)CCO

Synonyms

AZD-8835; AZD 8835; AZD8835

In Vitro

In vitro activity: AZD8835 is a potent inhibitor of PI3Kα (wild type, E545K and H1047R mutations) and PI3Kδ with excellent selectivity vs. PI3Kβ, PI3Kγ and an excellent general kinase selectivity. AZD8835 is a potent inhibitor of p-Akt in cells sensitive to PI3Kα inhibition (IC50=0.057 μM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50=0.049 μM in JeKo-1 B cell line), but not to cells sensitive to PI3Kβ inhibition (IC50=3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cell line) or PI3Kγ inhibition (IC50=0.53 μM in monocytic RAW264 cell line).

Kinase Assay: The selectivity profile of AZD8835 (Compound 25) among the class I PI3K isoforms is tested in enzyme and cell based assays. At the enzyme level, AZD8835 is a potent mixed inhibitor of PI3Kα (IC50 6.2 nM) and PI3Kδ (IC50 5.7 nM), with selectivity against PI3Kβ (IC50 431 nM) and PI3Kγ (IC5090 nM). AZD8835 is also a potent inhibitor of the commonly occurring PI3Kα mutants, PI3Kα- E545K (IC50 6 nM) and PI3Kα-H1047R (IC50 5.8 nM). In cell-based assays assessing the ability to inhibit Akt phosphorylation, AZD8835 is a potent inhibitor in cells sensitive to PI3Kα inhibition (IC50 57 nM in PIK3CA mutant human breast ductal carcinoma BT474 cell line) and in cells sensitive to PI3Kδ inhibition (IC50 49 nM in Jeko-1 B cell line, but not to cells sensitive to PI3Kβ inhibition (IC50 3.5 μM in PTEN null breast adenocarcinoma MDA-MB-468 cells) or to PI3Kγ inhibition (IC50 530 nM in monocytic RAW264 cell line).

Cell Assay: BT474, MCF7, or T47D cells are seeded in 384-well plates at a density of 500 to 2,000 cells per well and incubated overnight. Cells are dosed with compound(s) and cell confluency is measured at 4-hour intervals over several days.

In Vivo

AZD8835 has antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously and displays high metabolic stability and suitable physical properties for oral administration.

Animal model

CD1 mice

Formulation & Dosage

Prepared as a suspension in HPMC/Tween [0.5% hydroxypropyl methocellulose (Methocel (Colocorn))/0.1% Polysorbate 80]; 0.1 mL/10 g mouse; Oral administration

References

Mol Cancer Ther. 2016 May;15(5):877-89; Bioorg Med Chem Lett. 2015 Nov 15;25(22):5155-62; Curr Opin Pharmacol. 2015 Aug;23:82-91.