GDC-0941 dimethanesulfonate (Synonyms: GDC-0941 (2 MeSO3H salt);GDC0941 dimethanesulfonate;GDC-0941;GDC0941;GDC 0941)

Cell lines

MDA-MB-231 and SKBR3 cells

Preparation method

The solubility of this compound in DMSO is >10 mM. 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.

Reaction Conditions

10 μM for MDA-MB-231 cells 1.25 μM for SKBR3 cells 72 hours

Applications

The cytotoxicity was determined using MTT assay, after 72 h exposure to GDC-0941, ABT-737 and the combination. 10-times greater concentration of ABT-737 as a single agent resulted in a less than 50% increase in cytotoxicity. Regardless of the sensitivity to single agents, the combination of GDC-0941 and ABT-737 induced a more significant reduction of viable cells, indicating potent synergistic effect of GDC-0941 and ABT-737.

Animal models

Female severe combined immunodeficient mice injected with breast cancer cells

Dosage form

Oral administration, 100 or 150 mg/kg

Applications

GDC-0941 showed excellent antitumor activity in xenograft models with HER2 amplification, PIK3CA mutations, or concomitant alterations in two pathway components (e.g., PTEN loss and PIK3CA mutation), but little or no effect in xenografts of basal-like KRAS mutant MDA-MB-231 cells. Treatment with GDC-0941 at a dose of 100 mg/kg substantially down-regulated levels of pAKT(S473) in xenograft tumors of both sensitive KPL-4 cells and resistant MDA-MB-231 cells after 1 hour, suggesting effective pharmacodynamic inhibition of PI3K signaling at this dose in both models.

Other notes

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.

References:

[1] Zheng L, Yang W, Zhang C, et al. GDC-0941 sensitizes breast cancer to ABT-737 in vitro and in vivo through promoting the degradation of Mcl-1. Cancer letters, 2011, 309(1): 27-36.

[2] O'Brien C, Wallin J J, Sampath D, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clinical Cancer Research, 2010, 16(14): 3670-3683.