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| Targets |
Zamaporvint targets Porcupine, a membrane-bound O-acyltransferase that catalyzes the palmitoylation of Wnt ligands. Wnt palmitoylation is essential for Wnt ligand secretion and activation of Wnt signaling pathways. By inhibiting Porcupine, Zamaporvint blocks Wnt ligand palmitoylation, preventing secretion of active Wnt proteins and subsequent activation of Wnt/β-catenin signaling. The Wnt/β-catenin pathway is frequently dysregulated in various cancers, including colorectal, pancreatic, and other solid tumors. By targeting Porcupine, Zamaporvint effectively inhibits Wnt pathway activation at the ligand level, providing a mechanism to block Wnt signaling in tumors where the pathway is driven by ligand overexpression.
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| ln Vitro |
Zamaporvint (300 nM, 48 h) treatment of L-wnt3a cells decreased, with an IC50 of 64 pM, the conditioned medium's ability to activate the β-catenin-responsive luciferase reporter gene. This effect was concentration-dependent. Luciferase activity was restored upon the addition of recombinant Wnt3a, suggesting that downstream Wnt signaling was unaffected [1]. The impact of Zamaporvint (100 nM, 24 h) on proliferation is indicative of c-Myc mRNA downregulation that is concentration-dependent. has been found to have decreased immunosuppression at the same dose as after administration The auxiliary role of sex [1]. It also decreases the percentage of cells in S phase and strongly inhibits the expression of the mitotic marker phospho-histone-H3 in cells with abnormalities upstream of Wnt pathway components, indicating cell cycle arrest. In plasma, zamaprovint (20 μM, 18 h) varies between 2.5% and 7.5% across species, while microsomal CLint values span from 3.9 to 31.6 μL/min.mg, with mice and dogs having the lowest expected clearance rates. has the greatest clearance rate, while human and rodent clearance rates are lower [1]. In MDR1-MDCKII cells, zamaporvint (10 μM, 2 h) exhibits some efflux and good intrinsic permeability, but not in Caco-2 cells [1].
In vitro studies have demonstrated that Zamaporvint is a potent inhibitor of Wnt signaling with strong anti-proliferative effects in Wnt ligand-dependent cancer cell lines. The compound inhibits Wnt ligand palmitoylation and secretion, blocking autocrine and paracrine Wnt signaling. In colorectal and pancreatic cancer cell lines that depend on Wnt ligand expression, Zamaporvint treatment results in reduced cell proliferation and induction of apoptosis. The compound shows selectivity for Wnt ligand-dependent cells over cells with β-catenin-independent Wnt signaling. Zamaporvint's activity is concentration-dependent, with effective concentrations in the low nanomolar range. The compound exhibits multiple anti-tumor mechanisms. |
| ln Vivo |
In Wnt Inhibitory ligand-dependent SNU-1411, AsPC1, and HPAF II models, Zamaporvint (1.5 mg/kg or 5 mg/kg orally twice daily, or 5 mg/kg Zamaporvint orally once daily, for 28 days) reduces tumor growth and Wnt-responsive gene expression (including cMyc); tumor growth was unaffected in the Wnt ligand-independent HCT116 xenograft model[1]. In the B16F10 "cold" tumor model, zamaprovint (1.5 mg/kg, 5 mg/kg, once daily) inhibited immune evasion and decreased the number of Ki67-positive cells in the entire tumor area, with the impact being more noticeable in differentiated tumor areas[1]. Zamaporvint (1.5 or 5 mg/kg once daily) increases the percentage of regulatory T cells within CD8+/CT26 tumors, decreases B16F10 tumor-resident myeloid-derived suppressor cells, and collaborates with anti-programmed cell death protein-1 (PD-1, HY-P73361)[1]. Zamaporvint's pharmacokinetic characteristics in mice[1]
In vivo studies have demonstrated that Zamaporvint exhibits potent anti-tumor efficacy in preclinical models of Wnt-driven cancers. In mouse xenograft models of colorectal and pancreatic cancer, oral administration of Zamaporvint 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 (e.g., AXIN2, MYC). Zamaporvint shows favorable pharmacokinetic properties, supporting once-daily oral dosing. The compound has been evaluated in multiple preclinical models to assess its therapeutic potential for Wnt-driven malignancies. |
| Enzyme Assay |
Cell-free biochemical assays for Zamaporvint typically measure inhibition of Porcupine acyltransferase activity. A standard protocol involves incubating recombinant Porcupine enzyme with a Wnt substrate (e.g., Wnt3A), palmitoyl-CoA, and varying concentrations of Zamaporvint (0.1-1000 nM) in appropriate buffer. Palmitoylation of the Wnt protein is detected by autoradiography using [³H]-palmitoyl-CoA or by mass spectrometry. Alternatively, cell-free assays using membranes from Porcupine-expressing cells can be used. IC₅₀ values are determined from dose-response curves using nonlinear regression analysis. Assays are performed in triplicate with appropriate positive and negative controls.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: L-Wnt5a Tested Concentrations: 300 nM Incubation Duration: 48 h Experimental Results: Activated the β-catenin-responsive luciferase reporter gene in a concentration-dependent manner, with an IC50 of 64 pmol/L. Apoptosis Analysis[1] Cell Types: L-Wnt5a Tested Concentrations: 100 nM Incubation Duration: 24 h Experimental Results: Downregulated c-Myc mRNA and reduce the proportion of cells in S-phase, and strongly inhibited expression of the mitosis marker phospho-histone-H3 in cells with upstream aberrations in Wnt pathway components. Cellular assays for Zamaporvint typically use Wnt ligand-dependent cancer cell lines to assess inhibition of Wnt signaling. A standard protocol involves culturing cells (e.g., colorectal or pancreatic cancer cells) in 96-well plates, treating with Zamaporvint at concentrations ranging from 0.1-1000 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. Apoptosis is measured by caspase-3/7 activity or Annexin V staining. |
| Animal Protocol |
Animal/Disease Models: SCID-Beige mice were dosed at Translational Drug Discovery with vehicle[1]
Doses: 1.5 mg/kg or 5 mg/kg; 5 mg/kg Route of Administration: 1.5 mg/kg or 5 mg/kg orally twice (two times) daily, or 5 mg/kg RXC004 orally one time/day, for 28 days Experimental Results: decreased in tumor growth, and inhibition of Wnt-responsive gene expression including cMyc, was observed in the Wnt ligand– dependent SNU-1411, AsPC1, and HPAFII models. No effected tumor growth in the Wnt ligand–independent HCT116 xenograft mode. Animal/Disease Models: HPAF-II (5 × 106 cells; athymic nude mice), AsPC1 (3 × 106 cells; athymic nude mice), and SNU-1411 (1×107 cells; NOD-SCID mice) were implanted bilaterally, subcutaneously, whereas HCT116 (3 × 106 cells; athymic nude mice) were implanted in a single flank[1] Doses: Dosing was either 1.5 mg/kg twice (two times) daily RXC004 for 7–13 days then one time/day for the remainder of study (up to 29 days), or 28 days 1.5 mg/kg twice (two times) daily RXC004 for HCT116 Route of Administration: po Experimental Results: Demonstrated to inhibit tumor grow In vivo studies for Zamaporvint are typically conducted in mouse xenograft models of Wnt-driven cancers. A standard protocol involves subcutaneous implantation of colorectal or pancreatic cancer cells in immunocompromised mice. When tumors reach a volume of approximately 100-200 mm³, mice are randomized and treated with Zamaporvint administered orally at doses of 1-30 mg/kg, typically once 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 (AXIN2, MYC) by qPCR or immunohistochemistry. Pharmacodynamic effects are assessed in tumor tissues. |
| ADME/Pharmacokinetics |
Pharmacokinetic studies of Zamaporvint have demonstrated that the compound exhibits favorable PK properties with oral bioavailability. Following oral administration, Zamaporvint shows good absorption and systemic exposure, supporting once-daily dosing. The compound's half-life is sufficient for sustained target inhibition. Zamaporvint shows moderate plasma protein binding and distributes to target tissues. The compound's favorable PK profile has been characterized in preclinical species, enabling dose selection for efficacy studies. Detailed PK parameters including Cmax, Tmax, AUC, and half-life have been determined.
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| Toxicity/Toxicokinetics |
Toxicological studies of Zamaporvint 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, Zamaporvint 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 for homeostasis (e.g., intestinal crypts, 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 | |
| Additional Infomation |
Zamaporvint is an orally potent inhibitor of porcupine protein (PORCN) with potential antitumor activity. After oral administration, Zamaporvint binds to PORCN in the endoplasmic reticulum (ER) and inhibits its activity, thereby blocking the post-translational acylation modification of Wnt ligands and suppressing their secretion. This prevents Wnt ligand activation, interferes with Wnt-mediated signaling pathways, and inhibits Wnt-driven tumor cell growth. Porcupine protein is a membrane-bound O-acyltransferase (MBOAT) essential for Wnt ligand palmitoylation and plays a crucial role in Wnt ligand secretion and activity. The Wnt signaling pathway is aberrantly regulated in various cancers.
Zamaporvint (RXC004) is a research compound that has been evaluated in preclinical studies for the treatment of Wnt-driven cancers. As of the available information, Zamaporvint has been investigated in clinical trials for the treatment of advanced solid tumors. The compound was developed by Redx Pharma. Its mechanism of action—inhibition of Porcupine to block Wnt ligand secretion—represents a novel approach to targeting the Wnt pathway. Zamaporvint's favorable PK profile and potent anti-tumor activity make it a promising candidate for further clinical development. The compound is also a valuable research tool for studying Wnt signaling. |
| Molecular Formula |
C21H16F3N7O
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|---|---|
| Molecular Weight |
439.393253326416
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| Exact Mass |
439.136
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| CAS # |
1900754-56-4
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| PubChem CID |
121273514
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| Appearance |
White to off-white solid powder
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
32
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| Complexity |
637
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1N(CC(NC2=NC=C(C3=NC=CN=C3)C=C2)=O)C(C)=C(C2C=CN=C(C(F)(F)F)C=2)N=1
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| InChi Key |
QMLOYDPILBUVBV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H16F3N7O/c1-13-20(14-4-5-27-17(8-14)21(22,23)24)29-12-31(13)11-19(32)30-18-3-2-15(9-28-18)16-10-25-6-7-26-16/h2-10,12H,11H2,1H3,(H,28,30,32)
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| Chemical Name |
2-[5-methyl-4-[2-(trifluoromethyl)pyridin-4-yl]imidazol-1-yl]-N-(5-pyrazin-2-ylpyridin-2-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: 125 mg/mL (284.49 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 | 2.2759 mL | 11.3794 mL | 22.7588 mL | |
| 5 mM | 0.4552 mL | 2.2759 mL | 4.5518 mL | |
| 10 mM | 0.2276 mL | 1.1379 mL | 2.2759 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04907539
Conditions:Colorectal CancerLink: https://clinicaltrials.gov/ct2/show/NCT04907851
Conditions:Advanced Solid TumoursLink: https://clinicaltrials.gov/ct2/show/NCT03447470
Conditions:Cancer|Solid TumorProducts are for research use only; We do not sell to patients
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