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Purity: ≥98%
Taselisib (formerly also known as GDC-0032 or RG-7606), an imidazobenzoxazepin compound, is a novel and potent β-sparing small molecule inhibitor of PI3K with Ki values of 0.29 nM, 0.91 nM, 0.97 nM for PI3Kα, PI3Kβ and PI3Kγ, respectively. The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is dysfunctional, which promotes unchecked tumor growth. As a potential treatment for human malignancies, GDC-0032 has advanced to clinical trials and is currently being phase I evaluated. In HNSCC cell lines containing PIK3CA-activating aberrations, GDC-0032 has increased potency. Additionally, GDC-0032 and radiotherapy together were more effective at treating PIK3CA-altered HNSCC in vitro and in vivo than either treatment alone.
| Targets |
PI3Kδ (Ki = 0.12 nM); PI3Kα (Ki = 0.29 nM); PI3Kγ (Ki = 0.97 nM); PI3Kβ (Ki = 9.1 nM)
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| ln Vitro |
GDC-0032 is an orally bioavailable, powerful, and selective inhibitor of Class I PI3Kα, δ, and γ isoforms. It inhibits the PI3K β isoform by a factor of 30 less than the PI3Kα isoform. PI3Kα isoform (PIK3CA) mutant and HER2-amplified cancer cell lines are more active against GDC-0032, according to preclinical data. GDC-0032's IC50 value of 2.5 nM limits the growth of MCF7-neo/HER2 cells.[1]
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| ln Vivo |
GDC-0032 pharmacokinetics is approximately dose proportional and time independent with a mean t1/2 of 40 hours. The addition of GDC-0032 increases the activity of fulvestrant, causing tumor regressions and a 91% delay in tumor growth. The effectiveness of tamoxifen in vivo is also increased when GDC-0032 and tamoxifen are combined (102%TGI for GDC-0032).[1]
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| Enzyme Assay |
Enzymatic activity of the class I PI3K isoforms is measured using a fluorescence polarization assay that monitors formation of the product 3,4,5-inositoltriphosphate molecule as it competes with fluorescently labeled PIP3 for binding to the GRP-1 pleckstrin homology domain protein. As the labeled fluorophore is displaced from the GRP-1 protein binding site as the amount of phosphatidyl inositide-3-phosphate product increases, the fluorescence polarization signal decreases. As heterodimeric recombinant proteins, class I PI3K isoforms are expressed and purified. PIP3 detection reagents, di-C8-PIP2, and tetramethylrhodamine-labeled PIP3 (TAMRA-PIP3) are available from Echelon Biosciences. In the presence of 10 mM Tris (pH 7.5), 25 μM ATP, 9.75 mM PIP2, 5% glycerol, 4 mM MgCl2, 50 mM NaCl, 0.05% (v/v) Chaps, 1 mM dithiothreitol, and 2% (v/v) DMSO at 60 ng/mL, PI3K is measured under initial rate conditions. Before reading fluorescence polarization on an Envision plate reader, reactions are stopped with a final concentration of 9 mM EDTA, 4.5 nM TAMRA-PIP3, and 4.2 g/mL GRP-1 detector protein after the assay has been running for 30 min at 25 °C. The fit of the dose-response curves to a 4-parameter equation yields the IC50 values. Each value is the average of three experiments, and all of them have standard deviations that are below the geometric mean.
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| Cell Assay |
Taselisib (GDC-0032) is administered after cells are seeded in 96-well plates in replicates of six with 500–5,000 cells per well overnight. 4% glutaraldehyde is used to fix the cells for 30 minutes after the media have been removed after 4 days. After washing and dissolving in 10% acetic acid, fixed cells are stained with 0.1% crystal violet for 2 minutes.
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| Animal Protocol |
Six-week-old Nu/Nu mice receive bilateral injections of 5×105 cells resuspended in 200 μL of culture media and Matrigel combined in a 1:1 ratio. Mice are randomly assigned to treatment arms with 8–10 tumors each after the tumors have grown to a size of about 100–200 cm3. Daily oral gavage administration of taselisib (GDC-0032) (5 mg/kg) dissolved in a vehicle containing 0.5% methylcellulose and 0.2% TWEEN-80.
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| References |
| Molecular Formula |
C24H28N8O2
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|---|---|
| Molecular Weight |
460.5315
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| Exact Mass |
460.23352
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| Elemental Analysis |
C, 62.59; H, 6.13; N, 24.33; O, 6.95
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| CAS # |
1282512-48-4
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| Related CAS # |
1282512-48-4
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| Appearance |
White to off-white solid powder
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| SMILES |
CC1=NN(C(=N1)C2=CN3CCOC4=C(C3=N2)C=CC(=C4)C5=CN(N=C5)C(C)(C)C(=O)N)C(C)C
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| InChi Key |
BEUQXVWXFDOSAQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H28N8O2/c1-14(2)32-22(27-15(3)29-32)19-13-30-8-9-34-20-10-16(6-7-18(20)21(30)28-19)17-11-26-31(12-17)24(4,5)23(25)33/h6-7,10-14H,8-9H2,1-5H3,(H2,25,33)
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| Chemical Name |
2-methyl-2-[4-[2-(5-methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]propanamide
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| Synonyms |
RG7604; RG7604; RG 7604; GDC0032; GDC0032; GDC 0032
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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: 25~70 mg/mL (54.3~152 mM)
Ethanol: ~7 mg/mL (~15.2 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.43 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 (5.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (5.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1714 mL | 10.8571 mL | 21.7141 mL | |
| 5 mM | 0.4343 mL | 2.1714 mL | 4.3428 mL | |
| 10 mM | 0.2171 mL | 1.0857 mL | 2.1714 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 | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04439175 | Active Recruiting |
Drug: Taselisib | Advanced Lymphoma Refractory Lymphoma |
National Cancer Institute (NCI) |
February 25, 2016 | Phase 2 |
| NCT02390427 | Active Recruiting |
Drug: Taselisib Drug: Paclitaxel |
Recurrent Breast Cancer Metastatic Breast Cancer |
Otto Metzger, MD | April 20, 2015 | Phase 1 |
| NCT02465060 | Active Recruiting |
Drug: Afatinib Drug: Adavosertib |
Glioma Kidney Carcinoma |
National Cancer Institute (NCI) |
August 12, 2015 | Phase 2 |
| NCT02273973 | Completed | Drug: Taselisib Drug: Letrozole |
Breast Cancer | Genentech, Inc. | November 12, 2014 | Phase 2 |
| NCT02154490 | Completed | Drug: Taselisib Drug: Talazoparib |
Recurrent Squamous Cell Lung Carcinoma |
National Cancer Institute (NCI) |
July 8, 2014 |
 GDC-0032 has greater antiproliferative activity in cells containing activatingPIK3CAalterations, whereasPTENmutation or loss is associated with resistance to this agent.Clin Cancer Res.2016 Apr 15;22(8):2009-19. |
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 GDC-0032 enhances the G2–M checkpoint following irradiation in an ATR-dependent manner.Clin Cancer Res.2016 Apr 15;22(8):2009-19. |
 GDC-0032 enhances radiation-induced apoptosis and inhibits growth in head and neck cancer cell lines that are sensitive to its single-agent activity.Clin Cancer Res.2016 Apr 15;22(8):2009-19. |
 GDC-0032 decreases clonogenicity and impairs DNA damage in Cal-33 following irradiation.Clin Cancer Res.2016 Apr 15;22(8):2009-19. |
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 GDC-0032 is a more potent inhibitor of downstream AKT and mTOR signaling in head and neck cancer cell lines containingPIK3CA-activating alterations than in cell lines containingPTENalterations. |
 GDC-0032 potently impairs PI3K signaling and enhances the efficacy of fractionated radiotherapy in vivo.Clin Cancer Res.2016 Apr 15;22(8):2009-19. |
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