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| Targets |
Metabolite of Dasatinib; Src/Bcr-Abl
Dasatinib-C2-OH is a degradation product of dasatinib that can be used to form SNIPERs (Specific and Nongenetic IAP-dependent Protein Erasers). It binds to IAP (inhibitor of apoptosis protein) ligands via a linker to degrade the oncogenic kinase ABL. This approach represents a novel strategy for targeted protein degradation. It is also a metabolite of dasatinib. |
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| ln Vitro |
Chromosomal translocation occurs in some cancer cells, which results in the expression of aberrant oncogenic fusion proteins that include BCR-ABL in chronic myelogenous leukemia (CML). Inhibitors of ABL tyrosine kinase, such as imatinib and dasatinib, exhibit remarkable therapeutic effects, although emergence of drug resistance hampers the therapy during long-term treatment. An alternative approach to treat CML is to downregulate the BCR-ABL protein. We have devised a protein knockdown system by hybrid molecules named Specific and Non-genetic inhibitor of apoptosis protein [IAP]-dependent Protein Erasers (SNIPER), which is designed to induce IAP-mediated ubiquitylation and proteasomal degradation of target proteins, and a couple of SNIPER(ABL) against BCR-ABL protein have been developed recently. In this study, we tested various combinations of ABL inhibitors and IAP ligands, and the linker was optimized for protein knockdown activity of SNIPER(ABL). The resulting SNIPER(ABL)-39, in which dasatinib is conjugated to an IAP ligand LCL161 derivative by polyethylene glycol (PEG) × 3 linker, shows a potent activity to degrade the BCR-ABL protein. Mechanistic analysis suggested that both cellular inhibitor of apoptosis protein 1 (cIAP1) and X-linked inhibitor of apoptosis protein (XIAP) play a role in the degradation of BCR-ABL protein. Consistent with the degradation of BCR-ABL protein, the SNIPER(ABL)-39 inhibited the phosphorylation of signal transducer and activator of transcription 5 (STAT5) and Crk like proto-oncogene (CrkL), and suppressed the growth of BCR-ABL-positive CML cells. These results suggest that SNIPER(ABL)-39 could be a candidate for a degradation-based novel anti-cancer drug against BCR-ABL-positive CML[1].
In vitro, Dasatinib-C2-OH is used as a building block to synthesize SNIPERs that target ABL for degradation. Its activity is not typically measured as an inhibitor itself, but rather as a component of a protein-degrading molecule. The efficacy of the resulting SNIPERs is assessed by measuring the reduction in ABL protein levels in cells. |
| ln Vivo |
1.19 N-deshydroxyethyldasatinib pharmacokinetic characteristics in Wistar rats [2]. N-deshydroxyethyl dasatinib 2.05 8.7 23.9 2.0 10.293 0.072 Analyte Cmax (ng/mL) AUC0-t (h*ng/mL) AUC0-inf (h*ng/mL) Tmax (h) T1/2 (h) Kel (h-1)
In vivo, Dasatinib-C2-OH is a metabolite of dasatinib. As a metabolite, it may contribute to the overall pharmacological and toxicological profile of the parent drug. Its role in the formation of SNIPERs is a research application, and its in vivo efficacy would be evaluated in animal models of cancer to study the therapeutic potential of targeted protein degradation. |
| Enzyme Assay |
The in vitro assay for Dasatinib-C2-OH is not a direct activity assay but a synthetic assay. It is used as a chemical intermediate in the synthesis of SNIPERs. The compound is reacted with a linker and an IAP ligand to form the SNIPER molecule. The purity and identity of the SNIPER are confirmed by HPLC and mass spectrometry. The degradation of ABL by the SNIPER is then assessed in cell-based assays.
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| Cell Assay |
In vitro cell culture studies for Dasatinib-C2-OH are performed by treating cells with the SNIPERs synthesized from it. Cancer cell lines that express ABL, such as K562 cells, are treated with the SNIPER. The degradation of ABL protein is assessed by Western blotting. Cell viability and apoptosis are measured by MTT or CellTiter-Glo assays.
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| Animal Protocol |
Dasatinib is a multi-kinase inhibitor that potently inhibits Bcr-Abl, Src family and platelet-derived growth factor receptor kinases. Methotrexate is an antimetabolite and antifolate drug. Clinical trials utilizing a combination of dasatinib and methotrexate in patients with Philadelphia chromosome positive and/or Bcr-Abl positive acute lymphoblastic leukemia are currently ongoing. A need therefore exists to develop a sensitive analytical method for determination of dasatinib and methotrexate in plasma.To estimate methotrexate, dasatinib and its active metabolite N-deshydroxyethyl dasatinib simultaneously using liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) in Wistar rat plasma.The analytes were extracted by using liquid-liquid extraction procedure and separated on a reverse phase C18 column (50 mm×3 mm i.d., 4.6 µ) using methanol: 2 mM ammonium acetate buffer, pH 4.0 as mobile phase at a flow rate 1 mL/min in gradient mode. Selective reaction monitoring was performed using the transitions m/z 455.0>175.0, 488.1 > 401.0, 444.26>401.0, and 271.1>- 155.0 to quantify methotrexate, dasatinib, N-deshydroxyethyl dasatinib and tolbutamide respectively.The method was validated over the concentration range of 1-1 000 ng/mL and the lower limit of quantitation was 1 ng/mL. The recoveries from spiked control samples were > 79% for all analytes and internal standard Intra- and Interday accuracy and precision of validated method were within the acceptable limits of < 15% at all concentration.The quantitation method was successfully applied for simultaneous estimation of methotrexate, dasatinib and N- deshydroxyethyl dasatinib in a pharmacokinetic study in Wistar rats.[2]
In vivo animal experiments for Dasatinib-C2-OH would involve the administration of SNIPERs synthesized from it in xenograft models. The compound would be administered, and tumor growth would be monitored. The degradation of ABL in tumor tissues would be assessed by Western blotting or immunohistochemistry. The compound's ability to inhibit tumor growth and its pharmacokinetic properties would be evaluated. |
| ADME/Pharmacokinetics |
Dasatinib-C2-OH has a molecular formula of C20H22ClN7OS and a molecular weight of 444.0 g/mol. It is a solid compound that is soluble in DMSO. It is typically stored as a powder at -20°C for long-term stability. Its stability is maintained under recommended storage conditions. It is provided as both solid material and ready-to-use 10 mM solutions in DMSO.
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| Toxicity/Toxicokinetics |
Toxicological data for Dasatinib-C2-OH are limited, as it is a research compound and a metabolite. It is not intended for human use. Comprehensive toxicity studies have not been reported. Standard safety precautions for handling chemical reagents should be followed.
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| References |
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| Additional Infomation |
Dasatinib-C2-OH is a research compound with no clinical approval. It is a valuable tool for studying dasatinib metabolism and for developing targeted protein degradation strategies, particularly for the degradation of ABL. It is used in drug discovery programs to explore the therapeutic potential of SNIPERs for the treatment of cancers driven by ABL.
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| Molecular Formula |
C20H22CLN7OS
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|---|---|
| Molecular Weight |
443.95300
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| Exact Mass |
443.13
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| CAS # |
910297-51-7
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| Related CAS # |
N-Deshydroxyethyl Dasatinib-d8;1189998-96-6; Dasatinib N-oxide-d8;1189988-36-0; Dasatinib hydrochloride;854001-07-3;Dasatinib monohydrate;863127-77-9;Dasatinib-d8;1132093-70-9; 302962-49-8 (free); 2112837-79-1 (cabaldehyde); 910297-52-8 (N-oxide)
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| PubChem CID |
11669430
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| Appearance |
White to off-white solid powder
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| Density |
1.404g/cm3
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| Melting Point |
>300ºC
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| Index of Refraction |
1.69
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| LogP |
4.148
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
30
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| Complexity |
581
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DOBZFFWLHXORTB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H22ClN7OS/c1-12-4-3-5-14(21)18(12)27-19(29)15-11-23-20(30-15)26-16-10-17(25-13(2)24-16)28-8-6-22-7-9-28/h3-5,10-11,22H,6-9H2,1-2H3,(H,27,29)(H,23,24,25,26)
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| Chemical Name |
N-(2-chloro-6-methylphenyl)-2-[(2-methyl-6-piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide
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| Synonyms |
N-Deshydroxyethyl Dasatinib; 910297-51-7; BMS-528691; N-Deshydroxyethyl dasatinib metabolite M4; UNII-38T0L9673E; 38T0L9673E; N-(2-chloro-6-methylphenyl)-2-[(2-methyl-6-piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carboxamide; N-(2-chloro-6-methylphenyl)-2-[[2-methyl-6-(1-piperazinyl)-4-pyrimidinyl]amino]-5-thiazolecarboxamide;
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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 : ~55 mg/mL (~123.89 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.19 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 27.5 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: ≥ 2.75 mg/mL (6.19 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 27.5 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: ≥ 2.75 mg/mL (6.19 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 | 2.2525 mL | 11.2625 mL | 22.5251 mL | |
| 5 mM | 0.4505 mL | 2.2525 mL | 4.5050 mL | |
| 10 mM | 0.2253 mL | 1.1263 mL | 2.2525 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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