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| Targets |
BCR-ABL fusion protein. SNIPER(ABL)-020 is a degrader that targets the BCR-ABL oncoprotein. It consists of an ABL-binding moiety (derived from the inhibitor Dasatinib) linked to an IAP (Inhibitor of Apoptosis Protein) ligand (Bestatin). By binding to both IAP (an E3 ubiquitin ligase) and BCR-ABL, it promotes the ubiquitination and subsequent proteasomal degradation of the BCR-ABL protein.
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| ln Vitro |
In vitro, SNIPER(ABL)-020 effectively induces the reduction of the BCR-ABL protein in CML cell lines. Unlike an inhibitor that only blocks the kinase activity, this compound eliminates the entire oncoprotein. This degradation leads to potent anti-proliferative effects and can overcome resistance caused by mutations in the BCR-ABL kinase domain, as it removes the protein substrate for the mutated enzyme.
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| ln Vivo |
Detailed in vivo studies for SNIPER(ABL)-020 are limited. As a degrader of an established oncogene, it is expected to show anti-tumor activity in mouse xenograft models of CML. The degradation approach may offer a therapeutic advantage by providing a more complete and sustained blockade of the BCR-ABL signaling pathway compared to standard tyrosine kinase inhibitors (TKIs).
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| Enzyme Assay |
A non-cell-based ternary complex formation assay is performed. Recombinant His-tagged IAP (E3 ligase) and Flag-tagged BCR-ABL protein are mixed with increasing concentrations of SNIPER(ABL)-020 (0-1000 nM). After a 60-minute incubation at 4degC, the complex is pulled down using anti-Flag beads. The amount of IAP co-precipitated is analyzed by Western blot using an anti-His antibody, indicating the formation of the drug-induced ternary complex.
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| Cell Assay |
BCR-ABL-positive CML cells (e.g., K562 or KU812) are seeded in 6-well plates. Cells are treated with SNIPER(ABL)-020 at concentrations ranging from 0.1 nM to 1 uM for 24-48 hours. Cells are lysed and analyzed by Western blotting for BCR-ABL protein levels. The DC50 (half-maximal degradation concentration) is calculated by densitometry. Cell viability is measured after 72 h using an MTT or CellTiter-Glo assay.
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| Animal Protocol |
To evaluate in vivo activity, female NOD-SCID mice are injected intravenously with K562-luciferase cells to establish a disseminated CML model. After engraftment, mice are treated with SNIPER(ABL)-020 at 10-50 mg/kg (i.p., once daily). Tumor burden is monitored by bioluminescence imaging. In an alternative xenograft model, mice are treated for 14-21 days, and tumor tissues are collected to measure BCR-ABL degradation by Western blot.
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| ADME/Pharmacokinetics |
SNIPER(ABL)-020 is a research compound with a molecular weight of 947.50 (free base). It is soluble in DMSO and is typically formulated for in vivo studies in a vehicle containing PEG300, Tween-80, and saline. Pharmacokinetic studies are needed to determine its plasma half-life, but as a PROTAC molecule, it is expected to have a short to moderate half-life, typical for this class of compounds.
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| Toxicity/Toxicokinetics |
SNIPER(ABL)-020 is intended for research use only and is not approved for human therapeutic use. No formal toxicology studies are available. As a degrader of an oncogene, the primary expected effect is on cancer cells. However, potential off-target degradation of other proteins by the IAP ligand or the Dasatinib moiety could cause toxicity. Standard safety precautions for handling potent kinase inhibitors and degrader molecules should be taken.
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| References | |
| Additional Infomation |
SNIPER(ABL)-020 is a chemical probe used in targeted protein degradation research. It is not a drug candidate and has not entered clinical trials. This molecule is a research tool to explore the therapeutic potential of degrading BCR-ABL, particularly in the context of resistance to TKIs like Imatinib. It should be stored as a powder at -20degC, sealed and protected from light.
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| Molecular Formula |
C44H59CLN10O8S
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| Molecular Weight |
923.52
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| Appearance |
White to off-white solid powder
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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. |
| 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 :~200 mg/mL (~216.56 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (5.41 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 50.0 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: 5 mg/mL (5.41 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 50.0 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 | 1.0828 mL | 5.4141 mL | 10.8281 mL | |
| 5 mM | 0.2166 mL | 1.0828 mL | 2.1656 mL | |
| 10 mM | 0.1083 mL | 0.5414 mL | 1.0828 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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