| Size | Price | Stock | Qty |
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| 10mg |
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| 50mg |
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| 100mg |
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| Other Sizes |
| Targets |
GNF-6231 targets Porcupine (PORCN), a membrane-bound O-acyltransferase essential for Wnt ligand palmitoylation and secretion. Wnt palmitoylation is a critical post-translational modification required for Wnt ligand secretion and biological activity. By inhibiting Porcupine, GNF-6231 blocks Wnt ligand production, preventing activation of Wnt/β-catenin signaling. The Wnt pathway is frequently hyperactivated in various cancers, including breast, colorectal, and pancreatic cancers. GNF-6231 also inhibits Pron and endoplasmic reticulum proteins. The compound's high potency (IC₅₀ = 0.8 nM) and selectivity make it a valuable tool for studying Wnt signaling and developing Wnt-targeted therapies.
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| ln Vitro |
In vitro studies have demonstrated that GNF-6231 is a potent inhibitor of Porcupine with an IC₅₀ of 0.8 nM. In cultured cell reporter assays of Wnt signaling, the compound shows excellent pathway inhibition. GNF-6231 blocks Wnt ligand secretion and inhibits Wnt/β-catenin signaling in Wnt-dependent cancer cell lines. The compound's potency exceeds that of many other Porcupine inhibitors, with EC₅₀ values in the sub-nanomolar range. GNF-6231 has been used to study the role of Wnt signaling in cancer cell proliferation, differentiation, and stem cell maintenance. The compound shows selectivity for Wnt ligand-dependent cells over cells with β-catenin-independent Wnt signaling.
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| ln Vivo |
In vivo studies have demonstrated that GNF-6231 induces robust antitumor efficacy in mouse xenograft models. In MMTV-WNT1 transgenic mouse models and xenograft tumors driven by Wnt signaling, oral administration of GNF-6231 leads to significant tumor growth inhibition. The compound's efficacy is associated with reduced Wnt signaling in tumor tissues, as measured by decreased expression of Wnt target genes. GNF-6231's oral bioavailability supports convenient dosing regimens for in vivo studies. The compound has been evaluated in multiple preclinical models to assess its therapeutic potential for Wnt-driven malignancies.
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| Enzyme Assay |
Cell-free biochemical assays for GNF-6231 typically measure inhibition of Porcupine acyltransferase activity. A standard protocol involves incubating recombinant Porcupine enzyme or membranes from Porcupine-expressing cells with a Wnt substrate, palmitoyl-CoA, and varying concentrations of GNF-6231 (0.001-100 nM). Palmitoylation of the Wnt protein is detected by autoradiography using [³H]-palmitoyl-CoA or by mass spectrometry. IC₅₀ values are determined from dose-response curves using nonlinear regression analysis. Assays are performed in triplicate with appropriate positive and negative controls. The compound's purity and identity are verified by HPLC and NMR spectroscopy.
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| Cell Assay |
Cellular assays for GNF-6231 typically use Wnt signaling reporter systems and Wnt-dependent cancer cell lines. A standard protocol involves culturing cells in 96-well plates, treating with GNF-6231 at concentrations ranging from 0.01-100 nM for 24-72 hours. Wnt signaling activity is assessed using TCF/LEF reporter assays (e.g., TOPFlash/FOPFlash luciferase reporters). Wnt target gene expression is measured by qPCR for genes such as AXIN2, MYC, and LGR5. Cell proliferation is assessed by MTT or CellTiter-Glo assays. The compound's effects on Wnt ligand secretion can be measured by ELISA or Western blotting for Wnt proteins in conditioned media.
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| Animal Protocol |
In vivo studies for GNF-6231 are typically conducted in mouse xenograft models of Wnt-driven cancers. A standard protocol involves subcutaneous implantation of tumor cells (e.g., MMTV-WNT1-driven tumors) in immunocompromised mice. When tumors reach a volume of approximately 100-200 mm³, mice are randomized and treated with GNF-6231 administered orally at doses of 1-30 mg/kg, typically once or twice daily for 2-4 weeks. Tumor volume is measured with calipers twice weekly, and body weight is monitored for toxicity. At study termination, tumors are excised for analysis of Wnt signaling biomarkers by qPCR or immunohistochemistry. Pharmacodynamic effects are assessed in tumor tissues.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of GNF-6231 have demonstrated that the compound is orally bioavailable with favorable PK properties. Following oral administration, GNF-6231 shows good absorption and systemic exposure. The compound shows moderate binding to plasma proteins across species: mouse (88.0%), rat (83.1%), dog, monkey, and human. The compound's half-life and clearance support once- or twice-daily dosing. GNF-6231 distributes to target tissues, enabling effective inhibition of Porcupine in tumors. Detailed PK parameters including Cmax, Tmax, AUC, and half-life have been characterized in preclinical species.
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| Toxicity/Toxicokinetics |
Toxicological studies of GNF-6231 have been conducted as part of preclinical development. The compound's safety profile has been evaluated in rodent and non-rodent species. At therapeutic doses, GNF-6231 is generally well-tolerated with an acceptable safety margin. Observed toxicities are consistent with on-target Porcupine inhibition and include effects on tissues where Wnt signaling is important, such as the gastrointestinal tract and bone. The no-observed-adverse-effect level (NOAEL) has been established. Comprehensive toxicology assessments include clinical observations, clinical pathology, gross necropsy, and histopathology.
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| References |
[1]. Cheng D et al. Discovery of Pyridinyl Acetamide Derivatives as Potent, Selective, and Orally Bioavailable Porcupine Inhibitors. ACS Med Chem Lett. 2016 May 10;7(7):676-80.
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| Additional Infomation |
GNF-6231 is a research compound that has been evaluated in preclinical studies for the treatment of Wnt-driven cancers. The compound was developed by Genentech (GNF). As of the available information, GNF-6231 is in preclinical development and has not received regulatory approval for clinical use. The compound's high potency (IC₅₀ = 0.8 nM), selectivity, and oral bioavailability make it a promising candidate for further development. GNF-6231 is also a valuable research tool for studying Porcupine function and Wnt signaling. It is commercially available from suppliers for research purposes only.
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| Molecular Formula |
C24H25FN6O2
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| Molecular Weight |
448.49
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| Exact Mass |
448.202
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| CAS # |
1243245-18-2
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| PubChem CID |
46927297
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
746.0±60.0 °C at 760 mmHg
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| Flash Point |
405.0±32.9 °C
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| Vapour Pressure |
0.0±2.5 mmHg at 25°C
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| Index of Refraction |
1.627
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| LogP |
0.79
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
673
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC(=CN=C1C2=CC(=NC=C2)F)CC(=O)NC3=NC=C(C=C3)N4CCN(CC4)C(=O)C
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| InChi Key |
AXXNRMISICMFNS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H25FN6O2/c1-16-11-18(14-28-24(16)19-5-6-26-21(25)13-19)12-23(33)29-22-4-3-20(15-27-22)31-9-7-30(8-10-31)17(2)32/h3-6,11,13-15H,7-10,12H2,1-2H3,(H,27,29,33)
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| Chemical Name |
N-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]-2-[6-(2-fluoropyridin-4-yl)-5-methylpyridin-3-yl]acetamide
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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: ≥ 36 mg/mL (80.27 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (6.69 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 30.0 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: ≥ 3 mg/mL (6.69 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 30.0 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: ≥ 3 mg/mL (6.69 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 | 2.2297 mL | 11.1485 mL | 22.2970 mL | |
| 5 mM | 0.4459 mL | 2.2297 mL | 4.4594 mL | |
| 10 mM | 0.2230 mL | 1.1149 mL | 2.2297 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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