GDC-0032

Names

[ Name ]:
GDC-0032

[Synonym ]:
2-{4-[2-(1-Isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide
GDC-0032
RG7604
1H-Pyrazole-1-acetamide, 4-[5,6-dihydro-2-[3-methyl-1-(1-methylethyl)-1H-1,2,4-triazol-5-yl]imidazo[1,2-d][1,4]benzoxazepin-9-yl]-α,α-dimethyl-
S7103,GDC0032,RG7604
UNII-L08J2O299M
2-{3-[2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f ]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide
2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid
Taselisib

Biological Activity

[Description]:

Taselisib (GDC-0032) is a potent β-sparing small molecule inhibitor of PI3K, with Ki values of 0.29 nM, 0.91 nM, 0.97 nM for PI3Kα, PI3Kβ and PI3Kγ, respectively.

[Related Catalog]:

Research Areas >> Cancer

[Target]

PI3Kα:0.29 nM (Ki)

PI3Kβ:9.1 nM (Ki)

PI3Kδ:0.12 nM (Ki)

PI3Kγ:0.97 nM (Ki)

[In Vitro]

Taselisib (GDC-0032) (100 nM) inhibits AKT/mTOR signaling in PIK3CA mutant cell lines but not in cells with loss or mutation of PTEN; Taselisib (GDC-0032) enhances radiation-induced apoptosis and inhibits growth in head and neck cancer cell lines that are sensitive to its single-agent activiy[1]. Taselisib (GDC-0032) enhances the effects of MEK1/2 inhibition on both BRAFV600E/PTENNull human melanoma cells autochthonous mouse melanomas[2].

[In Vivo]

Taselisib (GDC-0032) (5 mg/kg, p.o.) potently impairs PI3K signaling and enhances the efficacy of fractionated radiotherapy; Taselisib (GDC-0032) and radiation is more effective than either treatment alone in nude mice implanted with subcutaneous Cal-33 xenografts[1]. The vehicle-treated BRAFV600E/PTENNull melanoma-bearing mice experiencs initial tumor regression after treatment with Taselisib (GDC-0032) (22.5 mg/kg, p.o.)[2].

[Cell Assay]

Cells are seeded in replicates of 6 in 96-well plates with 500 to 5,000 cells/well overnight and then treated with Taselisib (GDC-0032). After 4 days, the media are removed and the cells are fixed with 4% glutaraldehyde for 30 minutes. Fixed cells are stained with 0.1% crystal violet for 2 minutes, then washed, and dissolved in 10% acetic acid.

[Animal admin]

Six-week-old Nu/Nu mice are injected bilaterally with 5×105 cells resuspended in 200 μL of culture media and Matrigel mixed in a 1:1 ratio. After tumors reache approximately 100 to 200 cm3, mice are randomized into treatment arms with 8 to 10 tumors per group. Taselisib (GDC-0032) (5 mg/kg) is dissolved in a vehicle containing 0.5% methylcellulose with 0.2% TWEEN-80 and is administered via daily oral gavage.

[References]

[1]. Zachary S. Zumsteg, et al. Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating PIK3CA Alterations. Clin Cancer Res. 2016 Apr 15; 22(8): 2009–2019.

[2]. Marian M. Deuker, et al. PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF-Mutated Melanoma. Cancer Discov. 2015 Feb; 5(2): 143–153.

[3]. Ndubaku CO, et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a β-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem. 2013 Jun 13;56(11):4597-610.

[4]. Cocco E, et al. Dual CCNE1/PIK3CA targeting is synergistic in CCNE1-amplified/PIK3CA-mutated uterine serous carcinomas in vitro and in vivo. Br J Cancer. 2016 Jul 26;115(3):303-11.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.4±0.1 g/cm3

[ Boiling Point ]:
783.3±70.0 °C at 760 mmHg

[ Molecular Formula ]:
C₂₄H₂₈N₈O₂

[ Molecular Weight ]:
460.531

[ Flash Point ]:
427.5±35.7 °C

[ Exact Mass ]:
460.233521

[ PSA ]:
119.66000

[ LogP ]:
0.69

[ Vapour Pressure ]:
0.0±2.7 mmHg at 25°C

[ Index of Refraction ]:
1.709

[ Storage condition ]:
-20℃

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Related Compounds

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