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Purity: ≥98%
| Targets |
GNF-6231 targets Porcupine, a membrane-bound O-acyltransferase that is essential for the palmitoylation and secretion of Wnt proteins. By inhibiting Porcupine, it blocks Wnt signaling, which is tightly regulated in cell proliferation, differentiation, and embryonic morphogenesis. Aberrant activation of the Wnt pathway plays a critical role in various cancers including squamous cell carcinoma, breast cancer, and colorectal cancer.
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| ln Vitro |
In vitro activity: As an orally active and selective Porcupine inhibitor, GNF-6231 has no appreciable activities, at least up to 10 μM testing concentrations, for more than 200 off-targets, which include GPCRs, kinases, proteases, transporters, ion channels, and nuclear receptors. GNF-6231 shows IC50s of greater than 10 μM on all CYP isoforms tested (2C9, 2D6, 3A4). It shows high permeability in a Caco-2 human cell permeability assay with a possible efflux.
Kinase Assay: GNF-6231 is a potent and selective Porcupine inhibitor with an IC50 of 0.8 nM. Cell Assay: the TM3 Wnt-Luc and L-cell Wnt3A cells are co-cultured in a 384-well plate with DMEM supplemented with 2% (vol/vol) FBS and treated with different concentrations of compounds. After 24 h, the firefly luciferase activities are assayed with the Bright-Glo Luciferase Assay System. The IC50 is measured when the effect of the compound reduces the luminescence signal by 50%. In vitro, GNF-6231 shows no significant activity against over 200 off-targets including GPCRs, kinases, proteases, transporters, ion channels, and nuclear receptors at tested concentrations up to 10 μM. It shows IC50 >10 μM for all tested CYP isoforms (2C9, 2D6, 3A4). It demonstrates high permeability in Caco-2 human cell permeability assays. |
| ln Vivo |
GNF-6231 displays excellent pathway inhibition and induces robust antitumor efficacy in a mouse MMTV-WNT1 xenograft tumor model. GNF-6231 is moderately bound to mouse, rat, dog, monkey, and human plasma proteins (88.0, 83.1, 90.9, 71.2, and 95%, respectively). It shows good oral bioavailability, ranging from 72 to 96% in preclinical species (mouse, rat, and dog) when dosed in solution formulations. GNF-6231 is expected to have minimal to marginal distribution to tissues compared to total body water following intravenous administration to mouse (Vss 0.57 L/kg), rat (Vss 0.70 L/kg), and dog (Vss 0.25 L/kg).
In vivo, GNF-6231 demonstrates excellent pathway inhibition and robust antitumor efficacy in mouse MMTV-WNT1 xenograft tumor models. It shows moderate plasma protein binding across species (88.0% mouse, 83.1% rat, 90.9% dog, 71.2% monkey, 95% human). When administered as a solution formulation, it exhibits good oral bioavailability of 72% to 96% in preclinical species. |
| Enzyme Assay |
Porcupine inhibitory activity is determined using a Wnt3a co-culture RGA (reporter gene assay). TM3 Wnt-Luc and L-cell Wnt3A cells are co-cultured in 384-well plates with DMEM supplemented with 2% FBS and treated with varying concentrations of compound. After 24 hours, firefly luciferase activity is detected using Bright-Glo luciferase assay system.
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| Cell Assay |
TM3 Wnt-Luc and L-cell Wnt3A cells are co-cultured in 384-well plates and treated with different concentrations of compound. After 24 hours, firefly luciferase activity is detected using the Bright-Glo luciferase assay system. IC50 is measured when compound action reduces luminescence signal by 50%.
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| Animal Protocol |
Dissolved in 20% (vol/vol) PEG300 and 30% (vol/vol) 10% ETPGS in water; 3 mg/kg; p.o.
Nude mice GNF-6231 is dissolved in 20% (vol/vol) PEG300 and 30% (vol/vol) 10% ETPGS in water and administered at 3 mg/kg orally in nude mice. The MMTV-WNT1 xenograft tumor model is used to evaluate pathway inhibition and antitumor efficacy. |
| ADME/Pharmacokinetics |
GNF-6231 has the molecular formula C₂₅H₂₈N₆O₂ with a molecular weight of 444.53. It shows good oral bioavailability of 72% to 96% in preclinical species (mouse, rat, and dog) when administered as a solution formulation. It has low drug interaction potential with IC50 >10 μM for all tested CYP isoforms.
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| Toxicity/Toxicokinetics |
No specific toxicity data are detailed in the available references. However, the compound has demonstrated low/ no drug interaction potential with CYP isoforms. Its selectivity profile suggests a favorable safety margin for targeting Wnt signaling in cancer.
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| References |
ACS Med Chem Lett.2016 May 10;7(7):676-80.
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| Additional Infomation |
Porcupine inhibitors
GNF-6231 is a research compound not yet approved for clinical use. It is a potent and selective Porcupine inhibitor that blocks Wnt signaling, representing an attractive approach for treating various cancers with aberrant Wnt pathway activation. Its excellent oral bioavailability and low CYP interaction potential make it a promising candidate for further development. |
| Molecular Formula |
C25H28N6O2
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| Molecular Weight |
444.528824806213
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| Exact Mass |
444.227
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| CAS # |
1243244-74-7
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| PubChem CID |
46927217
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| Appearance |
White to off-white solid powder
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| LogP |
1.6
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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 |
33
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| Complexity |
667
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C)N1CCN(C2C=NC(=CC=2)NC(CC2=CN=C(C3C=CN=C(C)C=3)C(C)=C2)=O)CC1
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| InChi Key |
NEQNTAAQXJOQOM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H28N6O2/c1-17-12-20(15-28-25(17)21-6-7-26-18(2)13-21)14-24(33)29-23-5-4-22(16-27-23)31-10-8-30(9-11-31)19(3)32/h4-7,12-13,15-16H,8-11,14H2,1-3H3,(H,27,29,33)
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| Chemical Name |
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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) |
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 | 2.2496 mL | 11.2478 mL | 22.4957 mL | |
| 5 mM | 0.4499 mL | 2.2496 mL | 4.4991 mL | |
| 10 mM | 0.2250 mL | 1.1248 mL | 2.2496 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.
PK–PD relationship of19 (GNF-6231)in the mouse MMTV-Wnt1 tumor model (n= 3 per time point).ACS Med Chem Lett.2016 May 10;7(7):676-80. |
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 In vivoantitumor efficacy of19in the mouse MMTV-Wnt1 tumor model (n= 8 per group).ACS Med Chem Lett.2016 May 10;7(7):676-80. |
Structure–Activity Relationship of1.ACS Med Chem Lett.2016 May 10;7(7):676-80. |
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