| Size | Price | Stock | Qty |
|---|---|---|---|
| 50mg |
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| Other Sizes |
| Targets |
FLT-3
FLT3 (Fms-like tyrosine kinase 3) as a kinase inhibitor warhead. The desmorpholinyl modification may alter selectivity and potency. |
|---|---|
| ln Vitro |
The receptor tyrosine kinase FLT-3 is frequently mutated in acute myeloid leukemia; however, current small molecule inhibitors suffer from limited efficacy in the clinic. Conversion of a FLT-3 inhibitor (quizartinib) into a proteolysis targeting chimera (PROTAC) results in a compound that induces degradation of FLT-3 ITD mutant at low nanomolar concentrations. Furthermore, the PROTAC is capable of inhibiting cell growth more potently than the warhead alone while inhibiting fewer off-target kinases. This enhanced antiproliferative activity occurs, despite a slight reduction in the PROTAC's kinase inhibitory activity, via an increased level of apoptosis induction suggesting nonkinase roles for the FLT-3 ITD protein. Additionally, the PROTAC is capable of inducing FLT-3 ITD degradation in vivo. These results suggest that degradation of FLT-3 ITD may provide a useful method for therapeutic intervention.[1]
The desmorpholinyl quizartinib moiety retains FLT3 inhibitory activity, though the removal of morpholine may reduce potency compared to parent quizartinib (IC50 ~1-10 nM for wild-type FLT3). The PEG2-COOH group allows conjugation to E3 ligase ligands via amide bond formation. The compound is used to build PROTACs for FLT3 degradation in acute myeloid leukemia (AML). |
| ln Vivo |
PROTACs incorporating this warhead have shown in vivo degradation of FLT3 in mouse xenograft models, leading to tumor growth inhibition. The PEG2 linker provides a short, flexible spacer. The desmorpholinyl modification may improve metabolic stability. The intermediate itself is not a degrader; it must be conjugated to an E3 ligand. Specific in vivo data for this intermediate alone are limited.
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| Enzyme Assay |
FLT3 kinase inhibition is measured by an enzymatic assay. Recombinant FLT3 kinase (0.5-5 nM) is incubated with ATP (10 uM) and a peptide substrate, with varying concentrations of desmorpholinyl quizartinib-PEG2-COOH (0-1000 nM). Phosphorylation is detected by a luminescent kinase assay (e.g., ADP-Glo). IC50 is calculated. The PEG2-COOH group may slightly reduce potency (IC50 ~5-50 nM).
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| Cell Assay |
Cells expressing FLT3-ITD mutations (e.g., MV4-11 human AML cells) are treated with the compound alone or as part of a PROTAC (1-1000 nM) for 24-72 hours. FLT3 phosphorylation and total FLT3 levels are measured by Western blot. Cell viability is assessed by MTT. The compound alone inhibits FLT3 but does not induce degradation; the PROTAC induces degradation.
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| Animal Protocol |
In vivo efficacy of PROTACs derived from this warhead is evaluated in MV4-11 xenograft mice. The PROTAC (10-50 mg/kg, IV or IP) is administered. Tumor volume is measured. FLT3 degradation in tumor lysates is assessed by Western blot. The intermediate is not dosed alone. Pharmacokinetics of the PROTAC are characterized (t1/2, Cmax, AUC).
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| ADME/Pharmacokinetics |
Molecular weight: approximately 600-700 g/mol. The PEG2 spacer (MW ~88) increases water solubility slightly. The carboxylic acid group enables conjugation to amine-containing E3 ligands. The compound is stable at -20degC. PK data for the intermediate alone are not available; it is used only as a building block.
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| Toxicity/Toxicokinetics |
Quizartinib and its derivatives are generally well-tolerated at therapeutic doses but may cause QTc prolongation at high concentrations. The desmorpholinyl modification may reduce this risk. Acute toxicity studies are limited. Standard safety precautions for kinase inhibitors apply. The compound is for research use only, not for human therapy.
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| References | |
| Additional Infomation |
This compound is a research intermediate for FLT3-targeting PROTACs. Quizartinib is a potent FLT3 inhibitor approved in some regions for relapsed/refractory FLT3-ITD AML. The morpholino group is a common feature; desmorpholinyl analogs are used to explore structure-activity relationships. The PEG2-COOH warhead can be coupled to VHL or cereblon ligands to produce FLT3 degraders, which may overcome resistance mutations.
|
| Molecular Formula |
C30H33N5O7S
|
|---|---|
| Molecular Weight |
607.677325963974
|
| Exact Mass |
607.21
|
| CAS # |
2292116-14-2
|
| PubChem CID |
154729642
|
| Appearance |
Light yellow to yellow solid powder
|
| LogP |
5.2
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
14
|
| Heavy Atom Count |
43
|
| Complexity |
918
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC(C)(C)C1=CC(=NO1)NC(=O)NC2=CC=C(C=C2)C3=CN4C5=C(C=C(C=C5)OCCOCCOCCC(=O)O)SC4=N3
|
| InChi Key |
BMRGZWDBDUKFLR-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C30H33N5O7S/c1-30(2,3)25-17-26(34-42-25)33-28(38)31-20-6-4-19(5-7-20)22-18-35-23-9-8-21(16-24(23)43-29(35)32-22)41-15-14-40-13-12-39-11-10-27(36)37/h4-9,16-18H,10-15H2,1-3H3,(H,36,37)(H2,31,33,34,38)
|
| Chemical Name |
3-[2-[2-[2-[4-[(5-tert-butyl-1,2-oxazol-3-yl)carbamoylamino]phenyl]imidazo[2,1-b][1,3]benzothiazol-6-yl]oxyethoxy]ethoxy]propanoic acid
|
| Synonyms |
Desmorpholinyl Quizartinib-PEG2-COOH; 2292116-14-2; 3-(2-(2-((2-(4-(3-(5-(tert-Butyl)isoxazol-3-yl)ureido)phenyl)benzo[d]imidazo[2,1-b]thiazol-7-yl)oxy)ethoxy)ethoxy)propanoic acid;
|
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 1.6456 mL | 8.2280 mL | 16.4560 mL | |
| 5 mM | 0.3291 mL | 1.6456 mL | 3.2912 mL | |
| 10 mM | 0.1646 mL | 0.8228 mL | 1.6456 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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