product name GDC-0032
Description: GDC-0032 is a potent, next-generation β isoform-sparing PI3K inhibitor targeting PI3Kα/δ/γ with Ki of 0.29 nM/0.12 nM/0.97nM, >10 fold selective over PI3Kβ. In addition, GDC-0032 has been revealed to suppress the proliferative cellular activity with the EC50 value of 25nM and 571nM in MCF7 cells and PC3 cells, respectively. The IC50 values of GDC-0032 inhibiting cell activity are 4nM and 31nM in MCF7 cells and PC3 cells, respectively. In vivo, GDC-0032 has shown the inhibition of growth in MCF7-neo/Her2 xenograft model grown in nude mice.
References: J Med Chem. 2013 Jun 13;56(11):4597-610.
460.53
Formula
C24H28N8O2
CAS No.
1282512-48-4
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 70 mg/mL warming (152.0 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL
Solubility (In vivo)
Chemical Name
2-methyl-2-[4-[2-(5-methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]propanamide
other peoduct :
| In Vitro |
Kinase Assay: Enzymatic activity of the class I PI3K isoforms is measured using a fluorescence polarization assay that monitors formation of the product 3,4,5-inositoltriphosphate molecule as it competes with fluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homology domain protein. An increase in phosphatidyl inositide-3-phosphate product results in a decrease in fluorescence polarization signal as the labeled fluorophore is displaced from the GRP-1 protein binding site. Class I PI3K isoforms are expressed and purified as heterodimeric recombinant proteins. Tetramethylrhodamine-labeled PIP3 (TAMRA-PIP3), di-C8-PIP2, and PIP3 detection reagents are purchased from Echelon Biosciences. PI3Kα is assayed under initial rate conditions in the presence of 10 mM Tris (pH 7.5), 25 μM ATP, 9.75 μM PIP2, 5% glycerol, 4 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, and 2% (v/v) DMSO at 60 ng/mL. After assay for 30 min at 25 °C, reactions are terminated with a final concentration of 9 mM EDTA, 4.5 nM TAMRA-PIP3, and 4.2 μg/mL GRP-1 detector protein before reading fluorescence polarization on an Envision plate reader. IC50 values are calculated from the fit of the dose-response curves to a 4-parameter equation. Each reported value is an average of three experiments, and all have a standard deviation less than one geometric mean. Cell Assay: MCF7-neo/HER2 cells are seeded in 384-well plates in media at 1000 cells/well and incubated overnight prior to the addition of compounds to a final DMSO concentration of 0.5% v/v. MCF7-neo/HER2 cells are incubated for 3 and 4 days, respectively, prior to the addition of CellTiter-Glo reagent and reading of luminescence using an Analyst plate reader. For antiproliferative assays, a cytostatic agent such as aphidicolin and a cytotoxic agent such as staurosporine are included as controls. GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3Kα, δ, and γ isoforms, with 30 fold less inhibition of the PI3K β isoform relative to the PI3Kα isoform. Preclinical data show that GDC-0032 has increased activity against PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines. GDC-0032 inhibits MCF7-neo/HER2 cells proliferation with IC50 of 2.5 nM. |
|---|---|
| In Vivo | GDC-0032 pharmacokinetics is approximately dose proportional and time independent with a mean t1/2 of 40 hours. The combination of GDC-0032 enhances activity of fulvestrant resulting in tumor regressions and tumor growth delay (91% tumor growth inhibition (TGI)). In addition, the combination of GDC-0032 with tamoxifen enhances the efficacy of tamoxifen in vivo (102%TGI for GDC-0032). |
| Animal model | MCF7-neo/Her2 xenograft model |
| Formulation & Dosage | Dissolved in 0.5% methylcellulose with 0.2% Tween-80; 1.4, 2.8, 5.8, 11.25, or 22.5 mg/kg; Oral gavage |
| References | [1] Ndubaku CO, et al. J Med Chem, 2013, 56(11), 4597-4610. |
