Background
GDC-0032 is a novel and potent benzoxepin inhibitor of PI3Kα isoform with the Ki value of 0.29nM for PI3Kα[1].
GDC-0032 has been reported to potently inhibit PI3Kα and have the selectivity over other PI3Ks with the IC50 values of 0.29nM, 0.91nM and 0.97nM for PI3Kα, PI3Kβ and PI3Kγ, respectively. 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 [1].
参考文献:
[1] Ndubaku CO1, Heffron TP, Staben ST, Baumgardner M, Blaquiere N, Bradley E, Bull R, Do S, Dotson J, Dudley D, Edgar KA, Friedman LS, Goldsmith R, Heald RA, Kolesnikov A, Lee L, Lewis C, Nannini M, Nonomiya J, Pang J, Price S, Prior WW, Salphati L, Sideris S, Wallin JJ, Wang L, Wei B, Sampath D, Olivero AG. 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.
Protocol
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Cell experiment [1]:
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Cell lines
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MCF7-neo/HER2 cells
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Preparation method
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This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months.
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Reacting condition
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2.5 nM
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Applications
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In MCF7-neo/HER2 cells, GDC-0032 inhibited cell proliferation with an IC50 value of 2.5 nM.
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Animal experiment [1]:
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Animal models
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MCF7-neo/Her2 xenograft model
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Dosage form
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1.4, 2.8, 5.8, 11.25 or 22.5 mg/kg; p.o.; q.d., for 20 days
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Applications
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GDC-0032 dose-dependently increased TGI and tumor regressions. In addition, GDC-0032 was well-tolerated with less than 10% body weight loss observed when compared with the vehicle group.
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Other notes
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Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.
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参考文献:
[1]. Ndubaku CO1, Heffron TP, Staben ST, Baumgardner M, Blaquiere N, Bradley E, Bull R, Do S, Dotson J, Dudley D, Edgar KA, Friedman LS, Goldsmith R, Heald RA, Kolesnikov A, Lee L, Lewis C, Nannini M, Nonomiya J, Pang J, Price S, Prior WW, Salphati L, Sideris S, Wallin JJ, Wang L, Wei B, Sampath D, Olivero AG. 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.
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