GDC-0941

SKU: orb1306809

Description

Pictilisib (GDC-0941) is a potent, pan-class I PI3K inhibitor with IC50 values of 3, 33, 3, and 75 nM against p110α, β, δ, and γ isoforms, respectively. It is widely used in preclinical cancer research, demonstrating antitumor activity in both cellular assays and in vivo xenograft models.

Research Area

Cancer Biology

Key Properties

• CAS Number: 957054-30-7
• MW: 513.6
• Purity: >98%
• Formula: C₂₃H₂₇N₇O₃S₂
• SMILES: CS(=O)(=O)N1CCN(Cc2cc3nc(nc(N4CCOCC4)c3s2)-c2cccc3[nH]ncc23)CC1
• Target: Kinase
• Solubility: Soluble in DMSO (up to 60 mg/ml).

Bioactivity

• Target IC50:
  p110β:33 nM (cell free)|p110α-H1047R:3 nM|p110δ:3 nM (cell free)|DNA-PK:1.23 μM|mTOR:0.58 μM (Ki)|p110γ:75 nM|p110α-E545K:3 nM|p110α:3 nM (cell free)
• In Vivo:
  Treatment of animals bearing MCF7-neo/HER2 breast cancer xenografts with 7.5 mg/kg docetaxel or 150 mg/kg Pictilisib led to tumor growth delay and tumor stasis, respectively. The combination of 100 mg/kg Pictilisib and docetaxel resulted in tumor stasis during the treatment period that was sustained after dosing ended . AZD8055 (20mg/kg) or Pictilisib (75mg/kg) administration induced a transient increase in blood glucose levels. Treatment with either AZD8055 or Pictilisib led to a marked inhibition of Akt activity as well as phosphorylation of Thr308 and Ser473. Phosphorylation of the Akt substrates PRAS40 and Foxo-1/3a were also inhibited by AZD8055 or GDC-941 .
• In Vitro:
  Pictilisib is a potent inhibitor of cell proliferation in these cell lines with submicromolar IC50s. Potent inhibition of Akt (Ser473) phosphorylation was observed in U87MG, PC3, and MDA-MB-361 cells with IC50s of 46, 37, and 28 nM, respectively . In comparison to single-agent treatments, the combination of Pictilisib and docetaxel reduced tumor cell viability by 80% or greater in the breast cancer cell lines tested in vitro. A Bliss sum of 0 was determined in the MDA-MB-453 cell line indicating an additive combination effect whereas Bliss sums > 0 were calculated in the other tumor cell lines indicating a synergistic effect . Treatment with 250 nM Pictilisib for 2 hr resulted in 40%–85% inhibition of pAKT in all cell lines tested. Inhibition of the PI3K/AKT pathway by Pictilisib was reflected as a dose-dependent reduction in cell proliferation/viability. Pictilisib inhibited the growth of both trastuzumab-sensitive and -insensitive cells. The IC50 values for Pictilisib ranged between 150 and 950 nM and did not correlate with trastuzumab sensitivity .
• Cell Research:
  All drug treatments were tested in quadruplicate during a 4-day incubation period, and the relative number of viable cells was estimated using CellTiter-Glo. Total luminescence was measured on a Wallac Multilabel Reader. Cells were treated simultaneously with docetaxel (dose range = 0.0003–0.020 μmol/L) or GDC-0941 (dose range = 0.083–5 μmol/L) in an 8 × 10 matrix of concentrations chosen to encompass clinically relevant doses (24). The concentration of drug resulting in EC50 was determined using Prism software. Combination synergy of GDC-0941 and docetaxel was determined by Bliss independence analyses. A Bliss expectation for a combined response (C) was calculated by the equation: C = (A + B) (A × B) where A and B are the fractional growth inhibitions of drug A and B at a given dose. The difference between the Bliss expectation and the observed growth inhibition of the combination of drugs A and B at the same dose is the 'Delta.Bliss.' Delta.Bliss scores were summed across the dose matrix to generate a Bliss sum. Bliss sum = 0 indicates that the combination treatment is additive (as expected for independent pathway effects); Bliss sum > 0 indicates activity greater than additive (synergy); and Bliss sum < 0 indicates the combination is less than additive (antagonism). Statistical analysis comparing the Bliss sums for each cell line was conducted by the Student t-test .
• Animal Research:
  Female nu/nu mice were inoculated subcutaneously with MCF7-neo/HER2 or MX-1 breast cancer cells. When tumors reached a mean volume of 200 to 250 mm3, animals were size-matched and distributed into groups consisting of 10 animals per group. Docetaxel formulated in 3% EtOH, 97% saline was administered intravenously once weekly. GDC-0941, formulated in MCT (0.5% methylcellulose, 0.2% Tween-80) was dosed orally and daily. MAXF1162 is a HER2+/ER+/PR+ patient-derived breast cancer tumor xenograft model established by directly implanting tumors subcutaneously from patient to NMRI nu/nu mice. Tumor volume was calculated as follows: tumor size (mm3) = (longer measurement × shorter measurement2) × 0.5. Tumor sizes were recorded twice weekly over the course of a study. Following data analysis, P values were determined using the Dunnett t test. For pharmacodynamic studies, tumor samples (n = 4) were immediately frozen or fixed in 10% neutral-buffered formalin. Tumors were dissociated in cell extraction buffer, and lysates were analyzed by Western blotting as described above. Immunohistochemistry was conducted using 5-μm paraffin sections of formalin-fixed tissue on a Ventana Benchmark XT instrument by deparaffinization, treatment with antigen retrieval buffer, and incubation with anti-cleaved caspase-3 primary antibody at 37°C. Bound antibody was detected using DABMap technology, and sections were counterstained with hematoxylin .

Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

GNE-0941; Pictilisib

Compound Identifiers

PubChem CID

17755052