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| Targets |
Dynarrestin targets cytoplasmic dyneins 1 and 2, motor proteins responsible for minus-end-directed microtubule transport. It reversibly inhibits cytoplasmic dynein 1-dependent microtubule binding and motility. Additionally, it inhibits cytoplasmic dynein 2-dependent intraflagellar transport of the cargo IFT88 and flux of Smoothened within cilia without interfering with ciliogenesis. Dynarrestin also inhibits Hedgehog (Hh) signaling. Furthermore, it binds PTPIP51, leading to increased MAPK activation and blockade of Akt signaling.
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| ln Vitro |
In vitro, Dynarrestin inhibits Hedgehog signaling with an IC50 of 0.22 μM. It rapidly and reversibly inhibits endosome movement in living cells and perturbs mitosis by inducing spindle misorientation and pseudoprometaphase delay. It suppresses Hh-dependent proliferation of neuronal precursors and tumor cells. In Her2-positive breast cancer cells (SKBR3), Dynarrestin binds PTPIP51, leading to increased MAPK activation and complete blockade of Akt signaling. Dynarrestin inhibits tumor cell proliferation.
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| ln Vivo |
In vivo, Dynarrestin inhibits tumor cell proliferation in a mouse medulloblastoma model. It has shown anti-proliferative effects against neuronal precursors and tumor cells. The compound's ability to inhibit dynein-mediated transport and Hedgehog signaling contributes to its in vivo efficacy. Dynarrestin is for research use only and has not been approved for clinical therapeutic use.
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| Enzyme Assay |
In vitro enzyme/receptor binding assays for Dynarrestin typically involve measuring inhibition of dynein motor activity using microtubule gliding assays or motility assays. Inhibition of Hedgehog signaling can be assessed using cell-based reporter assays measuring Gli-dependent transcription. Binding to PTPIP51 can be evaluated using pull-down assays or surface plasmon resonance (SPR). IC50 values are calculated from dose-response curves.
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| Cell Assay |
For in vitro cellular assays, various cell lines including neuronal precursors, tumor cells, and SKBR3 breast cancer cells are cultured and treated with Dynarrestin. Hedgehog signaling inhibition is assessed using Gli-luciferase reporter assays. Cell proliferation is measured using MTT or ATP-lite assays. Mitotic defects and spindle misorientation are evaluated by immunofluorescence microscopy. Endosome movement is assessed by live-cell imaging.
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| Animal Protocol |
In vivo animal studies for Dynarrestin utilize mouse models, including medulloblastoma xenograft models. The compound is administered via intraperitoneal or other appropriate routes. Tumor volume is measured over time to assess inhibition of tumor cell proliferation. Pharmacodynamic endpoints may include assessment of Hedgehog signaling activity and dynein-mediated transport in tumor tissue. Efficacy is compared to vehicle controls.
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| ADME/Pharmacokinetics |
Dynarrestin has molecular weight of 431.50 g/mol and molecular formula C22H23F2N3O2S. It is soluble in DMSO (>40 mg/ml). The compound is a pale pink/purple solid with purity >98% by HPLC. It is typically stored at -20°C. Pharmacokinetic properties such as oral bioavailability and half-life would need to be determined in preclinical studies.
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| Toxicity/Toxicokinetics |
Preclinical toxicity of Dynarrestin has not been extensively documented. As a dynein inhibitor, potential adverse effects may include disruption of essential cellular processes such as mitosis and intracellular transport. The compound is for research use only and is not intended for therapeutic use. Standard toxicology studies would be required for therapeutic development. Safety pharmacology would assess effects on cell division and neuronal function.
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| References | |
| Additional Infomation |
Dynarrestin is a novel and potent inhibitor of cytoplasmic dyneins 1 and 2 and Hedgehog signaling. It is an aminothiazole compound that acts reversibly. Dynarrestin rapidly and reversibly inhibits dynein-dependent processes in living cells. It binds PTPIP51 leading to MAPK activation and Akt blockade in Her2-positive breast cancer cells. The compound is available for research purposes only.
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| Molecular Formula |
C22H23F2N3O2S
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| Molecular Weight |
431.4987
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| Exact Mass |
431.147
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| CAS # |
2222768-84-3
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| PubChem CID |
137919864
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| Appearance |
Light brown to brown solid powder
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| LogP |
6.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
30
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| Complexity |
547
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C(N([H])C2C([H])=C([H])C(=C([H])C=2F)F)=NC(=C1C(=O)OC([H])([H])C([H])([H])[H])C1C([H])=C([H])C(=C([H])C=1[H])N(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])[H]
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| InChi Key |
UZNNDDDSGCMQOQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H23F2N3O2S/c1-4-27(5-2)16-10-7-14(8-11-16)19-20(21(28)29-6-3)30-22(26-19)25-18-12-9-15(23)13-17(18)24/h7-13H,4-6H2,1-3H3,(H,25,26)
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| Chemical Name |
ethyl 4-[4-(diethylamino)phenyl]-2-(2,4-difluoroanilino)-1,3-thiazole-5-carboxylate
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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: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). This product is not stable in solution, please use freshly prepared working solution for optimal results. |
| 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 : ~83.33 mg/mL (~193.12 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 | 2.3175 mL | 11.5875 mL | 23.1750 mL | |
| 5 mM | 0.4635 mL | 2.3175 mL | 4.6350 mL | |
| 10 mM | 0.2317 mL | 1.1587 mL | 2.3175 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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