| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
IRAK4[1].
IRAK4 (interleukin-1 receptor-associated kinase 4) and IMiD substrates (Ikaros/Aiolos). KTX-951 is a PROTAC that simultaneously targets IRAK4 and the IMiD substrates Ikaros and Aiolos for degradation. It binds to IRAK4 and the E3 ubiquitin ligase cereblon, leading to ubiquitination and proteasomal degradation of IRAK4 (DC50 = 18 nM), Ikaros (DC50 = 14 nM), and Aiolos (DC50 = 13 nM). This dual degradation mechanism inhibits both the TLR/IL-1R pathway (via IRAK4 loss) and the expression of key transcription factors for multiple myeloma and other hematological cancers (via Ikaros/Aiolos loss). |
|---|---|
| ln Vitro |
In vitro, KTX-951 effectively degrades IRAK4 with a DC50 of 18 nM, and also degrades Ikaros and Aiolos with DC50 values of 14 nM and 13 nM, respectively. It inhibits cell proliferation in IRAK4- and IMiD-dependent cancer cell lines, including multiple myeloma (e.g., NCI-H929, OPM-2) and AML (e.g., MOLM-13). The half-maximal growth inhibitory concentration (GI50) is typically in the low nanomolar range, and the mechanism involves cell cycle arrest and apoptosis induction.
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| ln Vivo |
In vivo, KTX-951 (10 mg/kg, oral) shows oral bioavailability of 22% in a rat model. In xenograft mouse models of multiple myeloma and AML, oral administration of KTX-951 at doses of 30-100 mg/kg reduces tumor growth and causes tumor regression. Tumor tissues from treated animals show reduced levels of IRAK4, Ikaros, and Aiolos protein by immunoblotting, and decreased expression of downstream targets (e.g., IRF4, MYC). Survival is significantly prolonged compared to vehicle-treated controls.
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| Enzyme Assay |
To assess IRAK4 degradation, a cellular target engagement assay is performed: target cells (e.g., multiple myeloma cell lines) are treated with serially diluted KTX-951 (e.g., 1-1000 nM) for 4-24 hours. Cells are lysed, and IRAK4, Ikaros, and Aiolos protein levels are measured by immunoblotting (Western blot) using specific antibodies. GAPDH or beta-actin is used as a loading control. The DC50 values (concentration for 50% protein degradation) are calculated by densitometry of immunoblots. To assess kinase inhibition, a biochemical IRAK4 kinase assay is performed: purified IRAK4 enzyme is incubated with peptide substrate and ATP in the presence of KTX-951; phosphorylation is measured by a luminescent (ADP-Glo) or FRET-based detection method.
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| Cell Assay |
For in vitro cell viability assays, multiple myeloma (e.g., NCI-H929, OPM-2, MM.1S) and AML (e.g., MOLM-13, MV-4-11) cell lines are seeded into 96-well plates and treated with serially diluted KTX-951 (e.g., 1-1000 nM) for 72-96 hours. Cell viability is measured using an MTT or CellTiter-Glo luminescent assay. The half-maximal inhibitory concentration (IC50) is calculated from the dose-response curve. Apoptosis is assessed by flow cytometry using Annexin V/PI staining or by measuring caspase-3/7 activity. Cell cycle analysis is performed by propidium iodide (PI) staining.
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| Animal Protocol |
The in vivo efficacy is evaluated in a mouse xenograft model of multiple myeloma. Immunodeficient NSG mice are injected subcutaneously with NCI-H929 or OPM-2 cells. When tumors reach approximately 100-200 mm3, KTX-951 is administered orally at doses of 30-100 mg/kg once daily for 21-28 days. Tumor dimensions are measured with calipers twice weekly, and tumor volume is calculated. At the end of the study, tumors are harvested for immunoblotting (IRAK4, Ikaros, Aiolos, MYC, IRF4 levels) and for histopathological analysis (H&E staining, Ki-67 IHC, TUNEL assay). Body weight is monitored as a general indicator of toxicity. In an orthotopic model, survival (moribundity) is also monitored.
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| ADME/Pharmacokinetics |
KTX-951 has a molecular weight of 850.95 g/mol. It is orally bioavailable with an oral bioavailability (F%) of 22% in a rat model at 10 mg/kg. Detailed PK parameters (e.g., half-life, Cmax, AUC, clearance) are available in the literature. In rodents, the half-life is approximately 2-4 hours, and Cmax is dose-proportional. The compound shows high plasma protein binding. Solubility is 50 mg/mL in DMSO.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies indicate that KTX-951 is well-tolerated at efficacious doses. No significant adverse events or major organ toxicities have been reported at therapeutic dose levels in animal models. The safety profile is consistent with the dual degradation of IRAK4 and Ikaros/Aiolos, with manageable effects on lymphoid tissues at higher doses. Long-term safety studies are ongoing.
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| References | |
| Additional Infomation |
KTX-951 is a research-grade PROTAC that has not been approved for clinical use. It is currently in preclinical development for the treatment of hematological malignancies, including multiple myeloma and acute myeloid leukemia (AML). It is available for research purposes to study the combined degradation of IRAK4 and Ikaros/Aiolos as a therapeutic strategy in cancer, and to explore the mechanisms of PROTAC-mediated protein degradation.
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| Molecular Formula |
C46H52F2N8O6
|
|---|---|
| Molecular Weight |
850.951897621155
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| Exact Mass |
850.397
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| CAS # |
2573298-36-7
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| PubChem CID |
155437705
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
6.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
62
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| Complexity |
1680
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
C1(C(NC2C(OC)=CC3C(C=2)=CN(C2CCC(CN4CC[C@@]5(C[C@H](CCNC6=CC=CC7=C6C(=O)N(C6CCC(=O)NC6=O)C7=O)C5)CC4)CC2)N=3)=O)=NC(C(F)(F)C)=CC=C1
|
| InChi Key |
XMUGELSEEJWFAK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C46H52F2N8O6/c1-45(47,48)38-8-4-7-33(50-38)41(58)51-35-21-29-26-55(53-34(29)22-37(35)62-2)30-11-9-27(10-12-30)25-54-19-16-46(17-20-54)23-28(24-46)15-18-49-32-6-3-5-31-40(32)44(61)56(43(31)60)36-13-14-39(57)52-42(36)59/h3-8,21-22,26-28,30,36,49H,9-20,23-25H2,1-2H3,(H,51,58)(H,52,57,59)
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| Chemical Name |
6-(1,1-difluoroethyl)-N-[2-[4-[[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl]-7-azaspiro[3.5]nonan-7-yl]methyl]cyclohexyl]-6-methoxyindazol-5-yl]pyridine-2-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 |
| 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 (58.76 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 | 1.1752 mL | 5.8758 mL | 11.7516 mL | |
| 5 mM | 0.2350 mL | 1.1752 mL | 2.3503 mL | |
| 10 mM | 0.1175 mL | 0.5876 mL | 1.1752 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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