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Purity: ≥98%
GNE-477 is a novel, potent and efficacious dual inhibitor of PI3K (IC50=4 nM)/mTOR(Ki=21 nM). The PI3K/AKT/mTOR signaling pathway is regarded as an attractive area of research for the identification of oral small molecule inhibitors. PI3K-α, β, δ, and were all found to be inhibited in vitro by GNE-477, with IC50 values of 4, 86, 6, and 15 nM, respectively. A direct comparison of GNE-477 with its des-methyl analog in vivo showed that mice and dogs also exhibit the trend of decreased in vivo clearance that is seen in rats. In contrast to GNE-477, which had a low clearance in dogs, the des-methyl analog was cleared at a rate that was two-thirds that of hepatic blood flow. In a study evaluating the tumor growth inhibition of a PC3 tumor xenograft10 over a period of 14 days, stasis was reached at a dose of GNE-477 of 20 mg/kg QD, and significant inhibition was discovered with doses as low as 1 mg/kg QD. GNE-477 was generally well tolerated throughout this study, as evidenced by acceptable weight loss levels comparable to those in the vehicle cohort.
| Targets |
PI3Kα (IC50 = 4 nM); mTOR (IC50 = 21 nM)
GNE-477 (Compound 8) has improved potency in the MCF7.1 cell proliferation assay with an EC50 of 143 nM[1]. GNE-477 is a dual inhibitor of PI3K and mTOR kinase. It inhibits PI3K-α with an IC₅₀ of 4 nM, PI3K-β with an IC₅₀ of 86 nM, PI3K-δ with an IC₅₀ of 6 nM, PI3K-γ with an IC₅₀ of 15 nM, and mTOR kinase (Ki(app)) with a value of 21 nM. [1] |
|---|---|
| ln Vitro |
GNE-477 (Compound 8) has improved potency in the MCF7.1 cell proliferation assay with an EC50 of 143 nM[1].
GNE-477 inhibited the proliferation of MCF7.1 cells (a HER2-transfected clone of MCF7 with a PI3K E545K activating mutation) with an EC₅₀ of 15 nM. It also inhibited the proliferation of PC3 (a PTEN-negative cancer cell line) with an EC₅₀ of 174 nM. [1] GNE-477 inhibited the proliferation of MCF7.1 cells (a HER2-transfected clone of MCF7 with a PI3K E545K activating mutation) with an EC₅₀ of 15 nM. It also inhibited the proliferation of PC3 (a PTEN-negative cancer cell line) with an EC₅₀ of 174 nM. [1] |
| ln Vivo |
GNE-477 also exhibits stasis in a PC3 tumor growth inhibition study. In a 14-day experiment examining the tumor growth inhibition of a PC3 tumor xenograft, stasis is reached at a dose of 20 mg/kg QD, and significant inhibition is seen at doses as low as 1 mg/kg QD. The acceptable levels of weight loss comparable to those seen with the animals in the vehicle cohort during this study show that GNE-477 is generally well tolerated.[1]
In a PC3 tumor xenograft model in mice, oral administration of GNE-477 at 20 mg/kg once daily (QD) for 14 days resulted in tumor stasis. Significant tumor growth inhibition was observed at doses as low as 1 mg/kg QD. Partial responses (tumor volume reduction >50%) and complete responses (100% reduction) were observed in some animals during the study. [1] In a PC3 tumor xenograft model in mice, oral administration of GNE-477 at 20 mg/kg once daily (QD) for 14 days resulted in tumor stasis. Significant tumor growth inhibition was observed at doses as low as 1 mg/kg QD. Partial responses (tumor volume reduction >50%) and complete responses (100% reduction) were observed in some animals during the study. [1] |
| Enzyme Assay |
The biochemical potency against PI3K isoforms and mTOR kinase was determined using enzyme inhibition assays. [1]
The biochemical potency against PI3K isoforms and mTOR kinase was determined using enzyme inhibition assays. [1] |
| Cell Assay |
Cell proliferation assays were conducted using MCF7.1 and PC3 cell lines. Cells were treated with GNE-477, and proliferation was measured, likely using a viability or metabolic activity endpoint, to determine EC₅₀ values. [1]
Cell proliferation assays were conducted using MCF7.1 and PC3 cell lines. Cells were treated with GNE-477, and proliferation was measured, likely using a viability or metabolic activity endpoint, to determine EC₅₀ values. [1] |
| Animal Protocol |
Mice, Rats and Dogs[1]. The GNE-477 HCl salt is administered intravenously to female nu/nu mice (1 mg/kg) and orally to female nu/nu mice (5 mg/kg) as a solution in 80% PEG. The GNE-477 TFA salt is administered intravenously to male rats (1 mg/kg) and orally to male rats (5 mg/kg) as a solution in 80% PEG. The GNE-477 HCl salt is administered to male beagle dogs as an intravenous solution (1 mg/kg) in 10% HP-CD and as an oral suspension (2 mg/kg) in MCT. GNE-477's effectiveness in the PC3-NCI tumor xenograft model is studied. At the conclusion of the study (day 14), the percentage of tumor growth inhibition (TGI) is assessed and contrasted with the vehicle control group.
For the efficacy study, GNE-477 was formulated in a vehicle consisting of 0.5% methylcellulose and 0.2% Tween-80 (MCT). The compound was administered orally (po) once daily (QD) at doses of 1, 5, 20, and 75 mg/kg to mice bearing PC3 tumor xenografts. The study duration was 14 days. Tumor volumes and body weights were monitored. [1] For the efficacy study, GNE-477 was formulated in a vehicle consisting of 0.5% methylcellulose and 0.2% Tween-80 (MCT). The compound was administered orally (po) once daily (QD) at doses of 1, 5, 20, and 75 mg/kg to mice bearing PC3 tumor xenografts. The study duration was 14 days. Tumor volumes and body weights were monitored. [1] |
| ADME/Pharmacokinetics |
Compared with the demethylated analog (compound 1), GNE-477 showed improved in vivo clearance. In rats, the total plasma clearance (Cl) of GNE-477 was 22 mL/min/kg, the free clearance (Clu) was 220 mL/min/kg, and the plasma protein binding (PPB) was 90%. In mice, the total clearance was 34 mL/min/kg, the free clearance was 340 mL/min/kg, and the plasma protein binding was 90%. In dogs, the total clearance was 4 mL/min/kg, the free clearance was 80 mL/min/kg, and the plasma protein binding was 95%. The low clearance in dogs is particularly noteworthy compared with the high clearance of the demethylated analog. [1] In rats, the total plasma clearance (Cl) of GNE-477 was 22 mL/min/kg, the free clearance (Clu) was 220 mL/min/kg, and the plasma protein binding (PPB) was 90%. In mice, the total clearance was 34 mL/min/kg, the free clearance was 340 mL/min/kg, and the plasma protein binding was 90%. In dogs, the total clearance was 4 mL/min/kg, the free clearance was 80 mL/min/kg, and the plasma protein binding was 95%. The low clearance in dogs is particularly noteworthy compared to the high clearance of the demethylated analogue. [1]
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| Toxicity/Toxicokinetics |
In a 14-day PC3 xenograft efficacy study, GNE-477 treatment was generally well tolerated. Weight loss was within acceptable limits in all dose groups (including the excipient group), with a decrease of less than 10% compared to initial weight. [1]
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| References | |
| Additional Infomation |
GNE-477 is a 6-arylmorpholinothienopyrimidine derivative. It is a research result that improves the dissolution rate of high-melting-point PI3K inhibitors by adding a methyl group to the thienopyrimidine core to disrupt its planarity. This modification can usually reduce the in vivo clearance rate of different species while maintaining its strong enzymatic and cellular activity. It is a highly effective dual PI3K/mTOR inhibitor with good pharmacokinetic characteristics. [1]
|
| Molecular Formula |
C21H28N8O3S2
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|---|---|
| Molecular Weight |
504.62882
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| Exact Mass |
504.172
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| Elemental Analysis |
C, 49.98; H, 5.59; N, 22.21; O, 9.51; S, 12.71
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| CAS # |
1032754-81-6
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| Related CAS # |
1032754-81-6
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| PubChem CID |
25207689
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
693.6±65.0 °C at 760 mmHg
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| Flash Point |
373.3±34.3 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.717
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| LogP |
1
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| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
5
|
| Heavy Atom Count |
34
|
| Complexity |
779
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
NC1=NC=C(C2=NC(N3CCOCC3)=C4C(C(C)=C(CN5CCN(S(=O)(C)=O)CC5)S4)=N2)C=N1
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| InChi Key |
AKKCGLXULFRAET-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H28N8O3S2/c1-14-16(13-27-3-5-29(6-4-27)34(2,30)31)33-18-17(14)25-19(15-11-23-21(22)24-12-15)26-20(18)28-7-9-32-10-8-28/h11-12H,3-10,13H2,1-2H3,(H2,22,23,24)
|
| Chemical Name |
5-[7-methyl-6-[(4-methylsulfonylpiperazin-1-yl)methyl]-4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl]pyrimidin-2-amine
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| Synonyms |
GNE-477; GNE477; GNE 477
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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 ~16.7 mg/mL (33~49.5 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (3.31 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 16.7 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: ≥ 1.67 mg/mL (3.31 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 16.7 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9816 mL | 9.9082 mL | 19.8165 mL | |
| 5 mM | 0.3963 mL | 1.9816 mL | 3.9633 mL | |
| 10 mM | 0.1982 mL | 0.9908 mL | 1.9816 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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