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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. 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.
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
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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].
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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].
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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.
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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.
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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.
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References |
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Molecular Formula |
C23H27N7O3S2
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Molecular Weight |
513.6356
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Exact Mass |
513.16168
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Elemental Analysis |
C, 53.78; H, 5.30; N, 19.09; O, 9.34; S, 12.49
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CAS # |
957054-30-7
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Related CAS # |
Pictilisib dimethanesulfonate;957054-33-0
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Appearance |
White to off-white solid powder
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SMILES |
O=S(N1CCN(CC2=CC3=NC(C4=CC=CC5=C4C=NN5)=NC(N6CCOCC6)=C3S2)CC1)(C)=O
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InChi Key |
LHNIIDJUOCFXAP-UHFFFAOYSA-N
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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)
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Chemical Name |
4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine
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Synonyms |
Pictrelisib; Pictilisib; RG7321; RG-7321; RG 7321; GDC-0941; GDC 0941; GDC0941; GNE0941; GNE-0941; GNE 0941
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HS Tariff Code |
2934.99.9001
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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)
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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) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.87 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.87 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C,1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 2.5 mg/mL (4.87 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Solubility in Formulation 4: 2%DMSO+30%PEG 300+5%Tween 80+ddH2O: 5mg/mL Solubility in Formulation 5: 5 mg/mL (9.73 mM) in 0.5% MC 0.5% Tween-80 (add these co-solvents sequentially from left to right, and one by one), Suspened solution; with ultrasonication. |
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.
Calculation results
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.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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 |
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