| Size | Price | Stock | Qty |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg | |||
| Other Sizes |
| Targets |
IRAK4:50 nM (IC50)
Emavusertib targets IRAK4 (interleukin-1 receptor-associated kinase 4) with an IC₅₀ of 57 nM and FLT3 (FMS-like tyrosine kinase 3) with an IC₅₀ of <50 nM. Inhibition of IRAK4 leads to reduction in NF-κB activation and inflammatory cytokine production. The compound is selective for IRAK4 over FLT3. As a dual IRAK4/FLT3 inhibitor, emavusertib targets key signaling pathways involved in cancer cell survival, proliferation, and inflammation. |
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| ln Vitro |
When compared to IRAK-1, emavusertib (CA-4948) exhibits an over 500-fold selectivity for IRAK-4. With an IC50 of less than 250 nM, emavusertib decreases the release of TNF-α, IL-1β, IL-6, and IL-8 from TLR-stimulated THP-1 cells. Because emavusertib inhibits the receptor-type casein inhibitor FLT3, it still has binding antiproliferative action [1]. Emavusertib binds to IRAK-4 more strongly than it does to IRAK 1, 2, and 3. In marginal zone quiescent zone (MZL) cell lines, emavusertib (10 μM, 72 h) decreases the total number of proliferating cells and increases sub-G0 fractional motility [3]. Emavusertib (10 μM, 72 h) exhibits efficacy greater than 350 times [3]. can cause a noticeable rise in the quantity of MZL cells, particularly when taken in conjunction with Ibrutinib [3].
In vitro studies have demonstrated that Emavusertib is a potent IRAK4/FLT3 inhibitor with an IC₅₀ of 57 nM for IRAK4 and <50 nM for FLT3. The compound demonstrates good cellular activity in ABC DLBCL (activated B-cell diffuse large B-cell lymphoma) and AML (acute myeloid leukemia) cell lines. Inhibition of IRAK4 leads to reduction in NF-κB activation and inflammatory cytokine production in cell-based assays. The compound has shown anti-tumor activity in various cancer cell lines. |
| ln Vivo |
In animal models, emavusertib (CA-4948) has shown anticancer efficacy against cancers with mutations in the MyD88 gene. In FLT3 wild-type and FLT3 mutant acute myeloid leukemia (AML) animal models, emavusertib exhibits antileukemic action [1]. Emavusertib can decrease tumor growth in mice when given orally, once daily, for 14 days at a dose of 25–150 mg/kg [3].
In vivo studies have demonstrated that Emavusertib has anti-tumor activity in animal models. As an orally bioavailable compound, it is suitable for oral administration in preclinical studies. The compound's ability to inhibit IRAK4 and FLT3 translates to in vivo efficacy in cancer models, including ABC DLBCL and AML models. Reduction in NF-κB activation and inflammatory cytokine production has been observed in vivo following treatment. The compound is being investigated in clinical trials for hematological malignancies. |
| Enzyme Assay |
In vitro enzyme/receptor binding (non-cell) assays for Emavusertib involve kinase inhibition studies for IRAK4 and FLT3. Recombinant IRAK4 or FLT3 kinase domains are incubated with increasing concentrations of Emavusertib (0.1 nM - 10 μM), ATP, and a specific peptide substrate in kinase assay buffer (pH 7.4) at 30°C for 30-60 minutes. Phosphorylation of the substrate is measured using either radioactive ³³P-ATP incorporation (followed by filter binding and scintillation counting) or luminescence-based assays (e.g., ADP-Glo, Kinase-Glo). IC₅₀ values are calculated from dose-response curves by nonlinear regression. Selectivity profiling is performed using a panel of kinases at a fixed compound concentration (e.g., 1 μM). Positive controls (e.g., staurosporine) are included for assay validation.
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| Cell Assay |
For in vitro cell-based assays, ABC DLBCL and AML cell lines are cultured in appropriate media supplemented with fetal bovine serum and antibiotics. Cells are treated with Emavusertib at concentrations ranging from 0.1 nM - 10 μM for 24-72 hours. Cell viability is assessed by MTT, CCK-8, or CellTiter-Glo assays. NF-κB activation is measured by reporter gene assays (cells transfected with NF-κB luciferase reporter) or by quantifying p65 nuclear translocation using immunofluorescence. Inflammatory cytokine production (IL-6, TNF-α, IL-1β) in culture supernatants is measured by ELISA. Apoptosis is evaluated by Annexin V-FITC/PI staining, caspase-3/7 activity assays, and Western blot for PARP cleavage. Cell cycle analysis is performed by propidium iodide staining and flow cytometry.
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| Animal Protocol |
Animal/Disease Models: Mice bearing OCI-LY10 tumors[3]
Doses: 25, 50, or 150 mg/kg (one time/day), 12.5, 25, or 50 mg/kg (twice (two times) daily) Route of Administration: Orally, one time/day or twice (two times) daily , for 14 days Experimental Results: Induced tumor growth inhibition. Emavusertib administered as a twice-daily divided dose was equivalent to the corresponding once-daily dose with regards to antitumor activity, ie, 12.5 mg/kg BID versus 25 mg/kg QD. In vivo animal studies with Emavusertib typically use mouse xenograft models of ABC DLBCL or AML. Immunodeficient mice are subcutaneously or intravenously implanted with human cancer cells. When tumors are established, mice are treated with Emavusertib orally at doses ranging from 10-100 mg/kg once or twice daily for 2-4 weeks. Tumor volume and body weight are monitored regularly. At study endpoint, tumors are excised, weighed, and processed for histopathological and molecular analyses (immunohistochemistry for Ki-67, cleaved caspase-3, NF-κB). Blood samples are collected for pharmacokinetic analysis and assessment of inflammatory cytokine levels. Bone marrow and spleen are collected for flow cytometric analysis of leukemia burden in AML models. |
| ADME/Pharmacokinetics |
Emavusertib is an orally bioavailable compound suitable for once or twice daily dosing. As a small molecule kinase inhibitor, it has favorable pharmacokinetic properties including good oral absorption and appropriate half-life for therapeutic use. The compound has an IC₅₀ of 57 nM for IRAK4 and <50 nM for FLT3. The compound's selectivity for IRAK4 over FLT3 has been characterized. Pharmacokinetic parameters including Cmax, Tmax, AUC, and half-life are determined in preclinical species. The compound is metabolized primarily by hepatic enzymes, with elimination via biliary and renal routes.
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| Toxicity/Toxicokinetics |
Emavusertib has been evaluated in preclinical toxicology studies as part of its development as a therapeutic agent. As a kinase inhibitor, the compound is expected to have a manageable toxicity profile at therapeutic doses. Common adverse effects of kinase inhibitors may include gastrointestinal effects, fatigue, and hematological toxicities. The compound's selectivity for IRAK4 and FLT3 may minimize off-target effects. In preclinical studies, the compound has demonstrated a favorable safety profile with acceptable margins between efficacy and toxicity. Full toxicology data are available from the compound's development program.
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| References |
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| Additional Infomation |
Emavusertib is an orally bioavailable, reversible interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor with potential antitumor, immunomodulatory, and anti-inflammatory activities. After oral administration, Emavusertib targets and binds to IRAK4, blocking its kinase activity. This inhibits IRAK4-mediated signaling, preventing activation of the IRAK4-mediated nuclear factor-κB (NF-κB) signaling pathway and reducing the expression of inflammatory cytokines and certain pro-survival factors. This inhibits the proliferation of IRAK4-overactivated tumor cells, found in cells carrying MYD88 activating mutations or overactivated Toll-like receptor (TLR) pathways. Furthermore, CA-4948 may inhibit inflammation and immune-mediated cell destruction, particularly in inflammatory and autoimmune diseases with overactivated TLR or interleukin-1 receptor (IL-1R) signaling and dysregulated MYD88. IRAK4 is a serine/threonine protein kinase that plays a key role in both the TLR and IL-1R signaling pathways. It is activated by the adaptor protein MYD88 and links the TLR and IL-1R signaling pathways to the NF-κB pathway.
Emavusertib (CA-4948) is a first-in-class, orally bioavailable and highly potent IRAK4/FLT3 inhibitor with anticancer activity. It has an IC₅₀ of 57 nM for IRAK4. Inhibition of IRAK4 leads to reduction in NF-κB activation and inflammatory cytokine production. The compound demonstrates good cellular activity in ABC DLBCL and AML cell lines. Emavusertib is being developed as a potential therapeutic for hematological malignancies and has entered clinical trials. The compound is also known as CA-4948, AU-4948, and has the USAN name Emavusertib. It is not yet FDA-approved and is available for research purposes. |
| Molecular Formula |
C24H25N7O5
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|---|---|
| Molecular Weight |
491.499204397202
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| Exact Mass |
491.19
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| Elemental Analysis |
C, 58.65; H, 5.13; N, 19.95; O, 16.28
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| CAS # |
1801344-14-8
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| Related CAS # |
Emavusertib hydrochloride;2376399-42-5
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| PubChem CID |
118224491
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| Appearance |
Light yellow to green yellow solid powder
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| LogP |
1.7
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
36
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| Complexity |
773
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=NC=CC(=C1)C2=NC(=CO2)C(=O)NC3=CC4=C(N=C3N5CC[C@H](C5)O)N=C(O4)N6CCOCC6
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| InChi Key |
SJHNWSAWWOAWJH-MRXNPFEDSA-N
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| InChi Code |
InChI=1S/C24H25N7O5/c1-14-10-15(2-4-25-14)23-27-18(13-35-23)22(33)26-17-11-19-20(28-21(17)31-5-3-16(32)12-31)29-24(36-19)30-6-8-34-9-7-30/h2,4,10-11,13,16,32H,3,5-9,12H2,1H3,(H,26,33)/t16-/m1/s1
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| Chemical Name |
(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide
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| Synonyms |
CA4948 Emavusertib CA 4948 CA-4948
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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 : ~50 mg/mL (~101.73 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.23 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 20.8 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: 2.08 mg/mL (4.23 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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: ≥ 2.08 mg/mL (4.23 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 | 2.0346 mL | 10.1729 mL | 20.3459 mL | |
| 5 mM | 0.4069 mL | 2.0346 mL | 4.0692 mL | |
| 10 mM | 0.2035 mL | 1.0173 mL | 2.0346 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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