| Size | Price | Stock | Qty |
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| Targets |
ALK2
Zilurgisertib targets activin receptor-like kinase 2 (ALK2, also known as ACVR1), a serine/threonine kinase receptor that mediates signaling of BMP (bone morphogenetic protein) and activin pathways. ALK2 mutations are associated with fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by heterotopic ossification. By inhibiting ALK2 kinase activity (IC₅₀ = 15 nM), zilurgisertib blocks ALK2-mediated signaling, leading to inhibition of SMAD1/5 phosphorylation (IC₅₀ = 63 nM). This reduces hepcidin production and improves anemia. |
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| ln Vitro |
In vitro, zilurgisertib inhibits ALK2 kinase activity with an IC₅₀ of 15 nM and inhibits SMAD1/5 phosphorylation with an IC₅₀ of 63 nM. It inhibits BMP-6-stimulated hepcidin production in Huh-7 cells with an IC₅₀ of 20 nM. The compound's activity is assessed in cell-based assays measuring ALK2-mediated SMAD1/5 phosphorylation by Western blot or high-content imaging. Its selectivity for ALK2 over other kinases is confirmed through kinase panel screening. Zilurgisertib can be used in melanoma research.
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| ln Vivo |
In vivo, zilurgisertib is being developed as a treatment for fibrodysplasia ossificans progressiva (FOP) and for anemia due to myelofibrosis, myelodysplastic syndromes, and multiple myeloma. In Phase 1 clinical studies, zilurgisertib was generally well tolerated and exhibited a favorable pharmacokinetic profile amenable to once-daily dosing. The compound inhibits hepcidin production and improves anemia. Further in vivo studies are needed to fully characterize its efficacy across different indications.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for zilurgisertib typically involve kinase activity assays using purified ALK2 protein. The compound's ability to inhibit ALK2 kinase activity is assessed using radiometric or fluorescence-based kinase assays with appropriate peptide substrates. IC₅₀ values (15 nM for ALK2) are determined through dose-response experiments. Selectivity against other kinases is confirmed through parallel kinase panel screening. The compound's ability to inhibit SMAD1/5 phosphorylation is assessed in cell-based assays by Western blot.
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| Cell Assay |
In vitro cell-based assays for zilurgisertib utilize cell lines that express ALK2 and respond to BMP signaling. Cells are treated with varying concentrations of the compound for 24-48 hours. ALK2-mediated SMAD1/5 phosphorylation is measured by Western blot or high-content imaging. BMP-responsive reporter gene assays can also be employed. Hepcidin production is measured by ELISA in Huh-7 cells stimulated with BMP-6. The compound's effects on cell proliferation, differentiation, and gene expression can also be evaluated. Standard cell culture conditions (37°C, 5% CO₂) with appropriate media are employed.
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| Animal Protocol |
In vivo animal studies with zilurgisertib are conducted in rodent models of FOP, anemia, or other ALK2-driven conditions. The compound is administered orally at various doses. Endpoints include assessment of heterotopic ossification, measurement of hepcidin levels, evaluation of anemia markers, and pharmacokinetic profiling. Phase 1 clinical studies have evaluated zilurgisertib in healthy adults. All procedures must comply with institutional animal care and use guidelines.
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| ADME/Pharmacokinetics |
Zilurgisertib is orally bioavailable with favorable pharmacokinetic properties. In Phase 1 studies, zilurgisertib was rapidly absorbed with median Tmax of 2.0-4.1 hours post-dose. Exposure was more than dose proportional after single and multiple doses, suggesting non-linear pharmacokinetics. Plasma half-life values ranged from 22.8 to 31.4 hours, supporting once-daily dosing. No food effect was observed on zilurgisertib pharmacokinetics. Renal excretion was not the predominant pathway for elimination (16-27% of total clearance).
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| Toxicity/Toxicokinetics |
Zilurgisertib was generally well tolerated in Phase 1 studies, with adverse events generally of mild-to-moderate severity. As an investigational drug, it has undergone toxicological evaluation in preclinical studies. Common adverse effects may include gastrointestinal disturbances and other class-related effects. Patients should be monitored for potential side effects. Comprehensive safety data are available from clinical study reports. Zilurgisertib is for research use only and is not approved for human therapeutic applications.
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| References | |
| Additional Infomation |
Zilurgisertib is an activin A receptor type 1 (activin receptor-like kinase 2; ALK2; ALK-2; ACVR1; ACTR-I) inhibitor with potential anti-anemic and ossification-inhibiting effects. After administration, zilurgisertib targets and binds to ALK-2, inhibiting its activity. This blocks ALK2-mediated signaling and ALK2-mediated excessive bone morphogenetic protein (BMP) signaling. This may inhibit ectopic ossification (HO). Since ALK-2 enhances the secretion of the hepatic peptide hormone hepcidin, a key regulator of iron homeostasis, zilurgisertib reduces hepcidin expression in the liver, thereby increasing and restoring plasma iron levels, enhancing erythropoiesis, and correcting anemia of chronic disease (ACD). ALK2 is a serine/threonine receptor kinase and a type I cell surface receptor for bone morphogenetic protein (BMP). In diseases such as inflammation, various cancers, and progressive fibrous ossifying dysplasia (FOP), ALK2 is persistently activated due to activating mutations. Elevated serum hepcidin levels promote iron storage and reduce iron utilization, leading to iron deficiency anemia.
Zilurgisertib (INCB-000928; NBU-928) (CAS#: 2173389-57-4) is a potent, selective, orally bioavailable ALK2 inhibitor with an IC₅₀ of 15 nM for ALK2 and 63 nM for SMAD1/5 phosphorylation. It is being developed for FOP and anemia due to myelofibrosis, MDS, and multiple myeloma. Zilurgisertib inhibits hepcidin production and improves anemia. Phase 1 studies support once-daily dosing without regard to food. This compound is not a drug and has not received regulatory approval. |
| Molecular Formula |
C30H38N4O3
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|---|---|
| Molecular Weight |
502.647727489471
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| Exact Mass |
502.294
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| CAS # |
2173389-57-4
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| PubChem CID |
138628908
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
37
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| Complexity |
844
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O1CCC(CC1)N1C[C@H]2C[C@@]2(C2C=CC(C3C=NC(=C(C=3)C(NC34CCC(CC3)(CC4)O)=O)N)=CC=2)C1
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| InChi Key |
KPRPFTOLWQQUAV-OCVAFRRMSA-N
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| InChi Code |
InChI=1S/C30H38N4O3/c31-26-25(27(35)33-28-7-10-29(36,11-8-28)12-9-28)15-21(17-32-26)20-1-3-22(4-2-20)30-16-23(30)18-34(19-30)24-5-13-37-14-6-24/h1-4,15,17,23-24,36H,5-14,16,18-19H2,(H2,31,32)(H,33,35)/t23-,28?,29?,30+/m1/s1
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| Chemical Name |
2-amino-N-(4-hydroxy-1-bicyclo[2.2.2]octanyl)-5-[4-[(1R,5S)-3-(oxan-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl]phenyl]pyridine-3-carboxamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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: 100 mg/mL (198.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.97 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 25.0 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: ≥ 2.5 mg/mL (4.97 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 25.0 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 | 1.9895 mL | 9.9473 mL | 19.8946 mL | |
| 5 mM | 0.3979 mL | 1.9895 mL | 3.9789 mL | |
| 10 mM | 0.1989 mL | 0.9947 mL | 1.9895 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/NCT04455841
Conditions:Anemia|Post-essential Thrombocythemia Myelofibrosis|Post-polycythemia Vera MyelofibrosisLink: https://clinicaltrials.gov/ct2/show/NCT05090891
Conditions:Fibrodysplasia Ossificans Progressiva (FOP)Link: https://clinicaltrials.gov/ct2/show/NCT04582539
Conditions:Myelodysplastic Syndromes|Multiple Myeloma|Anemia
Title:Study to Evaluate the Pharmacokinetics, Safety, and Pharmacodynamics of INCB000928 in Participants With Impaired Renal Function and Hemodialysis
Status:Completed
updateDate:2023-05-15
Ctid:NCT05099445
Link: https://clinicaltrials.gov/ct2/show/NCT05099445
Conditions:Renal Impairment|HemodialysisProducts are for research use only; We do not sell to patients
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