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Purity: ≥98%
GNF-7 (GNF7; GNF 7) is a novel, potent, orally bioactive/bioavailable Bcr-Abl kinase inhibitor with potential anticancer activity. It inhibits the following kinases: M351T, T315I, E255 V, G250E and c-Abl, with IC50s of<5 nM, 61 nM, 122 nM, 136 nM, and 133 nM, respectively. It demonstrate significant in vivo antitumor efficacy in SCID beige female mice bearing T315I-Bcr-Abl-Ba/F3 orthotopic xenografts.
| ln Vitro |
Bcr-Abl mutants such T315I (IC50=11 nM), G250E (IC50<5 nM), E255V (IC50=10 nM), F317L (IC50<5 nM), and M351T (IC<5 nM) sub>50<5 nM) are all efficiently inhibited by GNF-7[2]. AKT/mTOR signaling is inhibited and GCK downstream by GNF-7 (1 μM; 2 hours) [3]. In NRAS mutant cell lines, GNF-7 (1 μM; 24 hours) causes apoptosis and cell cycle arrest [3].
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| ln Vivo |
In a bioluminescent xenograft mouse model, GNF-7 (10–20 mg/kg; op; daily; for 7 days) showed notable in vivo effectiveness against T315I Bcr-Abl [2]. GNF-7 has a limited oral bioavailability (36% in mice) and Cmax (3616 nM in mice) following oral treatment (20 mg/kg) [2]. Because GNF-7 has a high plasma clearance rate (8.6 mL/min/kg) following intravenous injection (5 mg/kg in mice), it has a terminal elimination half-life of 3.8 hours in mice [2].
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| Cell Assay |
Western Blot Analysis[3]
Cell Types: Ba/F3-NRAS-G12D cells, OCI-AML3 cells Tested Concentrations: 1 μM Incubation Duration: 2 hrs (hours) Experimental Results: Caused a diminished level of phosphorylation of p70S6K1, AKT (S473), JNK, and p38. Apoptosis Analysis[3] Cell Types: OCI-AML3 cells Tested Concentrations: 1 μM Incubation Duration: 24 hrs (hours) Experimental Results: Increased the levels of both cleaved PARP and cleaved caspase 3 and diminished bcl-2 and MCL1. Cell Cycle Analysis[3] Cell Types: OCI-AML3 cells Tested Concentrations: 1 μM Incubation Duration: 24 hrs (hours) Experimental Results: Induced of G0-G1 arrest. |
| Animal Protocol |
Animal/Disease Models: 6-8 weeks old SCID beige female mice, with Ba/F3-T315I-Bcr-Abl cells xenograft[2]
Doses: 10 mg/kg, 20 mg/kg Route of Administration: Oral administration, daily, for 7 days Experimental Results: Effectively inhibited tumor growth of T315I-Bcr-Abl-Ba/F3 cells in mice at low doses (10 mg/kg). Animal/Disease Models: 5-6 weeks old male balb/c (Bagg ALBino) mouse (20-25 g)[2] Doses: 5 mg/kg for iv; 20 mg/kg for ig (pharmacokinetic/PK Analysis) Route of Administration: intravenous (iv) injection and po (oral gavage) Experimental Results: Oral bioavailability (36%), Cmax (3616 nM), T1/2 (3.2 h). |
| References |
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| Molecular Formula |
C28H24F3N7O2
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|---|---|---|
| Molecular Weight |
547.53
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| Exact Mass |
547.194
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| Elemental Analysis |
C, 61.42; H, 4.42; F, 10.41; N, 17.91; O, 5.84
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| CAS # |
839706-07-9
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| Related CAS # |
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| PubChem CID |
11478363
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.655
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| LogP |
2.78
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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 |
5
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| Heavy Atom Count |
40
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| Complexity |
908
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=C(C(F)(F)F)C=CC=1)NC1C=C(N2CC3C(=NC(NC4C=CC(C)=NC=4)=NC=3)N(C)C2=O)C(C)=CC=1
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| InChi Key |
SZNYUUZOQHNEKB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H24F3N7O2/c1-16-7-9-21(34-25(39)18-5-4-6-20(11-18)28(29,30)31)12-23(16)38-15-19-13-33-26(36-24(19)37(3)27(38)40)35-22-10-8-17(2)32-14-22/h4-14H,15H2,1-3H3,(H,34,39)(H,33,35,36)
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| Chemical Name |
N-(4-methyl-3-(1-methyl-7-((6-methylpyridin-3-yl)amino)-2-oxo-1,4-dihydropyrimido[4,5-d]pyrimidin-3(2H)-yl)phenyl)-3-(trifluoromethyl)benzamide
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2 mg/mL (3.65 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 20.0 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 mg/mL (3.65 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 20.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8264 mL | 9.1319 mL | 18.2638 mL | |
| 5 mM | 0.3653 mL | 1.8264 mL | 3.6528 mL | |
| 10 mM | 0.1826 mL | 0.9132 mL | 1.8264 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.
Effect of GNF-7 suppression of AKT and/or GCK on induction of apoptosis and cell cycle. Blood. 2015 May 14; 125(20): 3133–3143. |
In vivo efficacy of GNF-7 in a xenotransplantation model and activity against primary AML patient samples. Blood. 2015 May 14; 125(20): 3133–3143. |
Identification of GCK as a functionally relevant target of GNF-7.Blood.2015 May 14;125(20):3133-43. |
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