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Purity: ≥98%
With a Ki of 0.2 nM, GDC-0326 is a brand-new, powerful, and selective PI3K (-Isoform of Phosphoinositide 3-Kinase) inhibitor. Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have drawn a lot of interest due to their potential application in the treatment of cancer. Despite the particular appeal of targeting PI3Kα , it has proven difficult to inhibit this isoform with selectivity. High selectivity is demonstrated by GDC-0326 versus other kinases. In humans, GDC-0326 has a low plasma CL. There are four class I PI3K isoforms (α, β, δ, and γ) ) in the PI3 kinase family. PI3K is the isoform of these that is most frequently linked to cancer.
| Targets |
PI3Kα (Ki = 0.2 nM); PI3Kβ (Ki = 26.6 nM); PI3Kδ (Ki = 4 nM); PI3Kγ (Ki = 10.2 nM)
The PI3Kα specific inhibitor GDC-0326 also achieves a very high level of selectivity over other kinases in addition to selectivity over the other class I isoforms. When tested on cytochrome P450 enzymes, GDC-0326 was not an inhibitor[1]. |
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| ln Vitro |
The PI3Kα specific inhibitor GDC-0326 also achieves a very high level of selectivity over other kinases in addition to selectivity over the other class I isoforms. When tested on cytochrome P450 enzymes, GDC-0326 was not an inhibitor[1].
Treatment of βTC3 cells (derived from RIP1-Tag2 mouse pancreatic neuroendocrine tumors) with 1 µM GDC-0326 for 2 hours reduced AKT phosphorylation, similar to the pan-PI3K inhibitor GDC-0941[2] In βTC3 cells, GDC-0326 (1 µM) induced apoptosis after 48 hours of treatment, as assessed by cleaved caspase-3 immunofluorescence[2] Pre-treatment of βTC3 and βTC4 cells with GDC-0326 (and BYL719, another p110α inhibitor) under low glucose conditions stimulated cell death[2] Incubation of mouse lung endothelial cells (ECs) with GDC-0326 reduced cell migration, but had no effect on cell proliferation or survival[2] |
| ln Vivo |
GDC-0326 has a consistently low clearance and a high oral bioavailability in all tested species, allowing for significant sustained free drug levels[1].
Daily oral administration of GDC-0326 (12 mg/kg/day) to RIP1-Tag2 mice (a model of pancreatic neuroendocrine tumors) from 12 to 14 weeks of age significantly improved animal lifespan compared to vehicle-treated controls[2] The same treatment regimen resulted in an approximately 60% reduction in total tumor burden[2] GDC-0326 treatment (12 mg/kg/day for 14 days) significantly reduced the incidence of liver micrometastases (0% vs. control) and lymph node (LN) metastasis (incidence reduced by four times) compared to vehicle-treated mice[2] For mice that did show LN infiltration, the average number of T antigen-positive nodes was also decreased (1.0 vs. 1.6 in controls)[2] Treatment did not alter tumor cell proliferation in vivo, as assessed by Ki67 immunostaining[2] Treatment led to a reduced number of hypervascularized “red islets”[2] Treatment significantly decreased tumor vascular area, indicating anti-angiogenic activity[2] Treatment resulted in an overall increase in tumor cell death, as assessed by TUNEL staining[2] |
| Cell Assay |
At 1 × 106 cells per dish, TC3 cells are plated. Cells are treated for 2 hours with vehicle, GDC-0941 (1 μM), GDC-0326 (1 μM), TGX-221 (0.5 μM), IC87114 (5 μM), BKM120 (0.8 μM) or BYL719 (1 μM) 24 hours later, after which they are lysed.
AKT phosphorylation assay: Exponentially growing βTC3 cells were treated with vehicle or GDC-0326 (1 µM) for 2 hours. Cells were then lysed, and total cell lysates were subjected to western blot analysis using antibodies against phospho-AKT (S473) and total AKT to assess inhibition of PI3K signaling[2] Apoptosis assay (Cleaved Caspase-3): βTC3 cells were treated with vehicle or GDC-0326 (1 µM) for 48 hours. Cells were then fixed and processed for immunofluorescence staining using an antibody against cleaved caspase-3. The percentage of cleaved caspase-3 positive cells was quantified to measure apoptosis[2] Cell death under low nutrients: βTC3 and βTC4 cells were treated with GDC-0326 under low glucose culture conditions. Cell death was assessed, although the specific assay method (e.g., viability dye, caspase activity) is not detailed in the main text[2] Endothelial cell migration assay: Mouse lung endothelial cells were incubated with GDC-0326. Their migratory capacity was assessed, while proliferation and survival were also monitored. The specific migration assay method (e.g., transwell, scratch wound) is not detailed[2] |
| Animal Protocol |
Mice: GDC-0326 is administered intravenously to female NCR nude mice at a dose of 1 mg/kg in a solution of 60% PEG400/ 10% ethanol and orally at a dose of 25 mg/kg in a solution of 0.5% methylcellulose/ 0.2% Tween 80 (MCT). Rats: 1 mg/kg of GDC-0326 prepared in 60% PEG400/10% ethanol is administered intravenously to male Sprague-Dawley rats. Male Sprague-Dawley rats are administered 5 mg/kg of GDC-0326 orally (PO) in a 0.5% methylcellulose/0.2% Tween 80 (MCT) solution.
Therapeutic efficacy study in RIP1-Tag2 mice: RIP1-Tag2 mice at 12 weeks of age were treated daily by oral gavage with GDC-0326 at a dose of 12 mg/kg/day. The compound was formulated in a vehicle consisting of 0.5% (w/v) methylcellulose and 0.2% (w/v) polysorbate 80 in de-ionized water. Treatment continued until the mice reached 14 weeks of age. Mice were then euthanized for analysis of tumor burden, metastasis, and tissue biomarkers[2] Pharmacodynamic study: RIP1-Tag2 mice bearing tumors were treated with a single dose of GDC-0326 (12 mg/kg, po) or vehicle. Mice were euthanized 3 hours post-dose, and individual tumors were harvested for western blot analysis to assess inhibition of AKT and S6 phosphorylation[2] |
| Toxicity/Toxicokinetics |
In the described in vivo studies, RIP1-Tag2 mice were orally administered 12 mg/kg/day of GDC-0326 daily for 2 weeks. The mice tolerated the treatment well and had significantly longer lifespans compared to the control group [2].
This article did not report specific toxic endpoints (e.g., weight loss, clinical observation, histopathology of major organs) or detailed toxicokinetic data for GDC-0326 [2]. |
| References | |
| Additional Infomation |
(2s)-2-({2-[1-(propyl-2-yl)-1h-1,2,4-triazol-5-yl]-5,6-dihydroimidazo[1,2-D][1,4]benzoxazol-9-yl}oxy)propionamide is an organic molecular entity.
GDC-0326 is a newly developed small molecule inhibitor selective for the p110α subtype of PI3K[2] Its antitumor activity in the RIP1-Tag2 pancreatic neuroendocrine tumor model is attributed to a dual mechanism: 1) direct pro-apoptotic effect on tumor cells (intrinsic mechanism); 2) significant anti-angiogenic effect mediated by endothelial cell function, leading to tumor angiogenesis reduction and subsequent tumor cell death[2] A key finding is that GDC-0326 can block tumor cell spread and metastasis in this model[2] This study provides a theoretical basis for selectively targeting p110α in pancreatic neuroendocrine tumors and suggests that this may be an alternative or complementary strategy to mTOR inhibition[2] |
| Molecular Formula |
C19H22N6O3
|
|---|---|
| Molecular Weight |
382.416383266449
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| Exact Mass |
382.175
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| Elemental Analysis |
C, 59.67; H, 5.80; N, 21.98; O, 12.55
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| CAS # |
1282514-88-8
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| Related CAS # |
1282514-88-8
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| PubChem CID |
58204997
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| Appearance |
White to off-white solid powder
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| LogP |
1.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
28
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| Complexity |
564
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| Defined Atom Stereocenter Count |
1
|
| SMILES |
C[C@@H](C(=O)N)OC1=CC2=C(C=C1)C3=NC(=CN3CCO2)C4=NC=NN4C(C)C
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| InChi Key |
SIKYDKLGPWRPMZ-LBPRGKRZSA-N
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| InChi Code |
InChI=1S/C19H22N6O3/c1-11(2)25-19(21-10-22-25)15-9-24-6-7-27-16-8-13(28-12(3)17(20)26)4-5-14(16)18(24)23-15/h4-5,8-12H,6-7H2,1-3H3,(H2,20,26)/t12-/m0/s1
|
| Chemical Name |
(2S)-2-[[2-(2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]oxy]propanamide
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| Synonyms |
GDC-0326; GDC 0326; GDC0326
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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: 76~100 mg/mL (198.7~261.5mM)
Ethanol: ~19 mg/mL (~49.7 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.54 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 (6.54 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 (6.54 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 | 2.6149 mL | 13.0746 mL | 26.1493 mL | |
| 5 mM | 0.5230 mL | 2.6149 mL | 5.2299 mL | |
| 10 mM | 0.2615 mL | 1.3075 mL | 2.6149 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.
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