Pictilisib (GDC0941, RG7321, GNE0941))

Alias: Pictrelisib; Pictilisib; RG7321; RG-7321; RG 7321; GDC-0941; GDC 0941; GDC0941; GNE0941; GNE-0941; GNE 0941
Cat No.:V0102 Purity: ≥98%
Pictilisib (also called GDC-0941, Pictrelisib, RG-7321 and GNE-0941) is a potent and orally bioavailable inhibitor of PI3Kα/δ (class I phosphatidylinositol 3 kinase) with IC50 of 3 nM in cell-free assays.
Pictilisib (GDC0941, RG7321, GNE0941)) Chemical Structure CAS No.: 957054-30-7
Product category: PI3K
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Pictilisib (GDC0941, RG7321, GNE0941)):

  • Pictilisib (GDC-0941) mesylate
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Pictilisib (also called GDC-0941, Pictrelisib, RG-7321 and GNE-0941) is a potent and orally bioavailable inhibitor of PI3Kα/δ (class I phosphatidylinositol 3 kinase) with IC50 of 3 nM in cell-free assays. It has the potential to be anti-cancer and demonstrated a modest level of selectivity against p110 (11-fold) and p110 (25-fold). Tumorigenesis is frequently linked to the activation of the PI3K/Akt signaling pathway. This pathway is frequently dysregulated in a variety of cancers, which may play a role in the resistance to many anticancer drugs. The creation of novel small molecules that specifically block the PI3K/Akt pathway might stop the growth of tumors. Phosphatidylinositol-3, 4, 5-triphosphate (PIP3) is a second messenger that carries PI3K downstream signals, and GDC-0941 is made to bind to the ATP-binding pocket of PI3K and prevent its synthesis. It engages in ATP-competitive binding to PI3K.

Biological Activity I Assay Protocols (From Reference)
Targets
p110α (IC50 = 3 nM); p110β (IC50 = 33 nM); p110δ (IC50 = 3 nM); p110γ (IC50 = 75 nM); p110α-H1047R (IC50 = 3 nM); p110α-E545K (IC50 = 3 nM); DNA-PK (IC50 = 1.23 μM); mTOR (Ki = 0.58 μM); Autophagy
ln Vitro
Pictilisib (GDC-0941) and RP-56976 reduce tumor cell viability by 80% or greater in the breast cancer cell lines than single-agent treatment. In the tumor models Hs578T1.2 (PI3K wild-type), MCF7-neo/HER2 (PI3K-mutant), and MX-1 (PTEN-null), GDC-0941 inhibits Akt phosphorylation as well as Akt signaling's downstream targets, such as pPRAS40 and pS6. The duration of RP-56976-induced mitotic arrest before apoptosis is shortened by pictilisib (GDC-0941)[1]. Pictilisib (GDC-0941) shows a high efficacy of antitumor activity in two ZD1839-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. Pictilisib (GDC-0941) is highly effective when combined with U0126 for inhibiting cell growth, G0-G1 arrest, and cell apoptosis. Pictilisib (GDC-0941) is relatively more toxic to A549 cells with wild-type PIK3CA than to H460 cells with activating mutations of PIK3CA[3]. As evidenced by a decline in pAK, pictilisib (GDC-0941) decreases PI3K pathway activity in both cell lines. Following hypoxic/anoxic exposure, pictilisib (GDC-0941) significantly lowers the amount of secreted VEGF that is found in the medium in all cells[4].
ln Vivo
Pictilisib (GDC-0941) (150 mg/kg, p.o.) leads to tumor stasis in MCF7-neo/HER2-bearing animals model. Pictilisib (GDC-0941) and RP-56976 result in tumor regressions during the treatment period leading to enhanced antitumor responses[1]. When Pictilisib (GDC-0941) treatment is stopped, the test cohort mice's tumors grow once more[2]. Tumors in the Pictilisib (GDC-0941)-treated mice exhibit a notable non-linear shrinkage. Pictilisib (GDC-0941) (25 or 50 mg/kg) reduces tumor growth and PI3K and HIF-1 pathway activity in eGFP-FTC133 tumor-bearing mice[4].
Enzyme Assay
Recombinant human PI3Kα, PI3Kβ, and PI3Kδ are coexpressed in a Sf9 baculovirus system with the p85α regulatory subunit and purified as GST-fusion proteins using affinity chromatography on glutathione-sepharose. Monomeric GST-fusions are used for both the expression and purification of recombinant human PI3Kγ . GDC-0941 is dissolved in DMSO and added to 20 mM Tris-HCl (pH 7.5) containing 200 μg yttrium silicate (Ysi) polylysine SPA beads, 4 mM MgCl2, 1 mM dithiothreitol (DTT), 1 μM ATP, 0.125 μCi [γ-33P]-ATP, and 4% (v/v) DMSO in a total volume of 50 μL. The kinase reaction is started in the assay mixture by adding the recombinant GST-fusion of PI3Kα (5 ng), PI3Kβ (5 ng), PI3Kδ (5 ng), or PI3Kγ (5 ng). The kinase reaction is stopped with 150 μL PBS following an hour of incubation at room temperature. It is then read using a Wallac Microbeta counter after being centrifuged for 2 minutes at 2000 rpm. A sigmoidal, dose-response curve fit in MDL Assay Explorer is used to determine the reported IC50 values.
Cell Assay
GDC-0941 is applied to cells for 48 and 72 hours at different concentrations. The CellTiter-Glo Luminescent Cell Viability Assay is used to identify cell viability and proliferation. By using a western blot, the pAkt (Ser473), cleaved caspase-3, and cleaved PARP are all examined. Apoptosis and caspase 3/7 activity are both detected using the Cell Death Detection ELISAplus assay and the Caspase-Glo 3/7 assay, respectively.
Animal Protocol
Female nu/nu mice are inoculated subcutaneously with MCF7-neo/HER2 or MX-1 breast cancer cells. Animals are distributed into groups of 10 animals each when tumors reach a mean volume of 200 to 250 mm3. Group sizes are determined by size matching. Once a week, intravenous RP-56976, a formulation of 3% EtOH and 97% saline, is given. Pictilisib (GDC-0941), a daily oral dose of MCT (0.5% methylcellulose, 0.2% Tween-80), is administered. By directly implanting tumors from patients under the skin of NMRI nu/nu mice, the MAXF1162 HER2+/ER+/PR+ patient-derived breast cancer tumor xenograft model was created. Volume of the tumor is calculated. Throughout a study, tumor size measurements are taken twice a week.
References

[1]. GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of RP-56976 in human breast cancer models by increasing cell death in vitro and in vivo.Clin Cancer Res. 2012 Jul 15;18(14):3901-11. Epub 2012 May 14.

[2]. Quantitative MRI establishes the efficacy of PI3K inhibitor (GDC-0941) multi-treatments in PTEN-deficient mice lymphoma.Anticancer Res. 2012 Feb;32(2):415-20.

[3].The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells.Mol Med Report. 2012 Feb;5(2):503-8.

[4]. GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways.J Clin Endocrinol Metab. 2011 Dec;96(12):E1934-43. Epub 2011 Oct

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C23H27N7O3S2
Molecular Weight
513.6356
Exact Mass
513.16168
Elemental Analysis
C, 53.78; H, 5.30; N, 19.09; O, 9.34; S, 12.49
CAS #
957054-30-7
Appearance
White to off-white solid powder
SMILES
O=S(N1CCN(CC2=CC3=NC(C4=CC=CC5=C4C=NN5)=NC(N6CCOCC6)=C3S2)CC1)(C)=O
InChi Key
LHNIIDJUOCFXAP-UHFFFAOYSA-N
InChi Code
InChI=1S/C23H27N7O3S2/c1-35(31,32)30-7-5-28(6-8-30)15-16-13-20-21(34-16)23(29-9-11-33-12-10-29)26-22(25-20)17-3-2-4-19-18(17)14-24-27-19/h2-4,13-14H,5-12,15H2,1H3,(H,24,27)
Chemical Name
4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine
Synonyms
Pictrelisib; Pictilisib; RG7321; RG-7321; RG 7321; GDC-0941; GDC 0941; GDC0941; GNE0941; GNE-0941; GNE 0941
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~44 mg/mL (85.66 mM)
Water: <1 mg/mL (slightly soluble or insoluble)
Ethanol: <1 mg/mL (slightly soluble or insoluble)
Solubility (In Vivo)
2%DMSO+30%PEG 300+5%Tween 80+ddH2O: 5mg/mL (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9469 mL 9.7344 mL 19.4689 mL
5 mM 0.3894 mL 1.9469 mL 3.8938 mL
10 mM 0.1947 mL 0.9734 mL 1.9469 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Working concentration mg/mL;

Method for preparing DMSO stock solution mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

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Clinical Trial Information
NCT Number Status Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00960960 Completed Drug: Bevacizumab
Drug: Pictilisib
Breast Cancer Genentech, Inc. August 2009 Phase 1
NCT01493843 Completed Drug: pictilisib
Drug: Placebo
Non-Small Cell Lung Cancer Genentech, Inc. January 20, 2012 Phase 2
Biological Data
  • Pictilisib (GDC-0941)

  • Pictilisib (GDC-0941)
  • Pictilisib (GDC-0941)
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