| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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Purity: ≥98%
GNE-493 is a novel, potent, selective, and orally bioavailable dual pan-PI3-kinase/mTOR inhibitor with IC50s of 3.4 nM, 12 nM, 16 nM, 16 nM and 32 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR. The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.
| ln Vitro |
GNE-493 is a powerful pan-PI3 kinase and mTOR dual inhibitor with a low molecular weight. The inhibitory effects of GNE-493 on class I PI3K isoforms are approximately comparable. The Invitrogen SelectScreen service was utilized to screen GNE-493 against a 142-kin panel. Out of these kinases, only three showed greater than 50% inhibition from GNE-493, and none showed greater than 80% inhibition at 1 μM. GNE-493 is more than 100 times more selective for PI3Kα than these three unrelated kinases (Aurora A IC50>10 μM, MLK1 IC50=591 nM, and SYK IC50=371 nM), according to a subsequent IC50 study [1].
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| ln Vivo |
In order to verify and evaluate GNE-493's in vivo effectiveness, it was tested in a human MCF7.1 breast cancer xenograft model that contained activating mutations in PI3Kα. GNE-493 (10 mg/kg) was given orally once daily for 21 days to mice that were carrying xenografts. At day 21, 10 mg/kg of GNE-493 inhibited tumor growth by 73% in comparison to vehicle control animals, which is in line with findings in the PC3 prostate cancer xenograft model. GNE-493 has a similar effectiveness profile against MCF7.1 breast cancers and exhibits similar PI3K pathway inhibition when achieving comparable drug exposure levels [1].
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| References |
| Molecular Formula |
C17H20N6O2S
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|---|---|
| Molecular Weight |
372.4447
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| Exact Mass |
372.136
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| CAS # |
1033735-94-2
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| PubChem CID |
25242324
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| Appearance |
Off-white to gray solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
585.0±60.0 °C at 760 mmHg
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| Flash Point |
307.6±32.9 °C
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| Vapour Pressure |
0.0±1.7 mmHg at 25°C
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| Index of Refraction |
1.687
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| LogP |
1.02
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
484
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
LEXMMFPAPDGYGZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H20N6O2S/c1-17(2,24)12-7-11-13(26-12)15(23-3-5-25-6-4-23)22-14(21-11)10-8-19-16(18)20-9-10/h7-9,24H,3-6H2,1-2H3,(H2,18,19,20)
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| Chemical Name |
2-(2-(2-aminopyrimidin-5-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-ol
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| Synonyms |
GNE493; GNE-493; GNE 493
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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 : ~45 mg/mL (~120.82 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6850 mL | 13.4250 mL | 26.8500 mL | |
| 5 mM | 0.5370 mL | 2.6850 mL | 5.3700 mL | |
| 10 mM | 0.2685 mL | 1.3425 mL | 2.6850 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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