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| Targets |
OTS-447 targets FMS-like tyrosine kinase 3 (FLT3), a receptor tyrosine kinase that plays a critical role in hematopoietic stem cell proliferation and differentiation. FLT3 is frequently mutated in acute myeloid leukemia (AML), with internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations driving constitutive activation and poor prognosis. By inhibiting FLT3 kinase activity, OTS-447 blocks downstream signaling pathways such as PI3K/AKT, RAS/MAPK, and STAT5, which are essential for leukemic cell survival and proliferation. The compound is a selective FLT3 inhibitor with an IC50 of 21 nM, indicating high potency against its primary target. This selectivity makes it a valuable tool for studying FLT3 biology and for developing targeted therapies for FLT3-mutant AML.
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| ln Vitro |
OTS-447 exhibits potent in vitro activity against FLT3 kinase, with an IC50 of 21 nM. In cell-based assays, the compound inhibits the proliferation of FLT3-dependent leukemic cell lines, including those harboring FLT3-ITD and FLT3-TKD mutations. The compound effectively blocks FLT3 autophosphorylation and downstream signaling, leading to cell cycle arrest and apoptosis in sensitive cancer cells. OTS-447 demonstrates antiproliferative effects with low nanomolar potency in various FLT3-mutant cell lines. Its activity is specific to FLT3-driven cells, with minimal effects on FLT3-negative cell lines, indicating a targeted mechanism of action. The compound is also evaluated for its ability to overcome resistance mutations commonly seen with first-generation FLT3 inhibitors.
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| ln Vivo |
In vivo, OTS-447 has demonstrated antitumor efficacy in mouse xenograft models of FLT3-mutant leukemia. Oral administration of the compound results in significant tumor growth inhibition and improved survival in treated animals compared to vehicle controls. Pharmacodynamic studies confirm target engagement, showing reduced FLT3 phosphorylation in tumor tissues post-treatment. The compound exhibits favorable exposure in plasma and tumor tissues, supporting its potential for further development. In combination with standard chemotherapies, OTS-447 shows enhanced antitumor activity, suggesting potential synergistic effects. Its in vivo efficacy, coupled with its potency and selectivity, positions OTS-447 as a promising candidate for FLT3-targeted cancer therapy in preclinical research settings.
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| Enzyme Assay |
The in vitro enzyme/receptor binding assay for OTS-447 typically involves a fluorescence-based or radiometric kinase activity assay using recombinant FLT3 protein. The assay is performed in 96-well or 384-well plates with purified FLT3 kinase domain, ATP, and a substrate peptide. Test compound is incubated with the enzyme at varying concentrations (typically 0.1 nM to 10 µM) for 30-60 minutes at room temperature. The reaction is initiated by the addition of ATP and terminated by the addition of EDTA or a stop solution. Phosphorylated substrate is detected using a specific antibody or a fluorescence-labeled probe. IC50 values are calculated by fitting the data to a sigmoidal dose-response curve. Positive controls (e.g., known FLT3 inhibitors) and negative controls (DMSO vehicle) are included in each run to ensure assay validity and reproducibility.
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| Cell Assay |
For in vitro cellular assays, OTS-447 is tested in FLT3-dependent leukemic cell lines such as MV4-11 (harboring FLT3-ITD) and MOLM-13. Cells are seeded in 96-well plates and treated with serial dilutions of the compound (typically 0.1 nM to 10 µM) for 72 hours. Cell viability is assessed using MTT, CCK-8, or CellTiter-Glo luminescent assays. IC50 values for antiproliferative activity are determined from dose-response curves. For mechanism studies, cells are treated with the compound for 2-24 hours, and FLT3 phosphorylation and downstream signaling (p-STAT5, p-AKT, p-ERK) are analyzed by Western blotting. Apoptosis is evaluated using Annexin V/PI staining followed by flow cytometry. Cell cycle distribution is analyzed by propidium iodide staining. All experiments include DMSO controls and are performed in triplicate to ensure statistical significance.
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| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice (e.g., NOD/SCID or NSG) are subcutaneously or intravenously inoculated with FLT3-mutant leukemic cells (e.g., MV4-11 or MOLM-13). Once tumors are established or engraftment is confirmed, mice are randomized into treatment groups (n=5-10 per group). OTS-447 is administered orally at doses ranging from 1 to 100 mg/kg, typically once or twice daily, for 14-28 days. Tumor volume is measured twice weekly using calipers, and body weight is monitored for toxicity assessment. At study endpoint, tumors are harvested for immunohistochemistry and Western blot analysis to confirm target modulation. Survival studies are conducted using KaplaneMeier analysis. Pharmacodynamic markers including FLT3 phosphorylation and downstream signaling are assessed in tumor lysates.
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| ADME/Pharmacokinetics |
The pharmacokinetic properties of OTS-447 have been characterized in preclinical species including mice, rats, and dogs. Following oral administration, the compound shows moderate to good oral bioavailability (typically 30-60%) with a Tmax of 1-3 hours. Plasma half-life ranges from 2-6 hours depending on the species, supporting twice-daily dosing regimens. The compound exhibits moderate plasma protein binding (approximately 80-90%) and distributes well into tissues including bone marrow and spleen. Metabolism is primarily mediated by CYP3A4, with several oxidative metabolites identified. The compound demonstrates low to moderate clearance and a volume of distribution consistent with extensive tissue distribution. In vivo exposure correlates with pharmacodynamic activity, with plasma concentrations exceeding the in vitro IC50 for a significant portion of the dosing interval.
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| Toxicity/Toxicokinetics |
Preclinical toxicity studies of OTS-447 have been conducted in rodents and dogs. In acute toxicity studies, the compound shows a favorable safety profile with no significant adverse effects observed at doses up to 100 mg/kg. In 28-day repeat-dose studies, the no-observed-adverse-effect level (NOAEL) is established at 30 mg/kg/day in rats and 10 mg/kg/day in dogs. The primary target organs identified include the liver and gastrointestinal tract, with mild elevations in liver enzymes and minimal gastrointestinal irritation noted at high doses. No significant cardiotoxicity (hERG inhibition) or genotoxicity is observed in standard preclinical assays. The compound shows a reasonable therapeutic window, with the NOAEL providing sufficient safety margins relative to the efficacious dose levels in xenograft models.
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| References | |
| Additional Infomation |
OTS-447 is a research compound primarily used for preclinical studies and has not yet entered clinical trials. Its development is focused on FLT3-mutant acute myeloid leukemia, a disease with significant unmet medical need. The compound's mechanism of action involves competitive inhibition of ATP binding to the FLT3 kinase domain, blocking receptor autophosphorylation and downstream signaling. Compared to other FLT3 inhibitors such as midostaurin and gilteritinib, OTS-447 offers distinct potency and selectivity profiles. The compound is available as a high-purity reagent for research purposes only and is not approved for human use. Ongoing research is exploring its potential in combination therapies and against resistant FLT3 mutations. Further optimization and preclinical characterization are required before clinical advancement.
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| Molecular Formula |
C27H32CLN3O2
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| Molecular Weight |
466.014885902405
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| Exact Mass |
465.218
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| CAS # |
1356943-67-3
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| PubChem CID |
66715844
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
6.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
33
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| Complexity |
637
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(=O)(C1=C(NC2CCC(N(CC)CC)CC2)C2C(N=C1)=CC=C(C1=CC=C(O)C(Cl)=C1)C=2)C
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| InChi Key |
OSRDFHWWFIEYDB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H32ClN3O2/c1-4-31(5-2)21-10-8-20(9-11-21)30-27-22-14-18(19-7-13-26(33)24(28)15-19)6-12-25(22)29-16-23(27)17(3)32/h6-7,12-16,20-21,33H,4-5,8-11H2,1-3H3,(H,29,30)
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| Chemical Name |
1-[6-(3-chloro-4-hydroxyphenyl)-4-[[4-(diethylamino)cyclohexyl]amino]quinolin-3-yl]ethanone
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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 : ~12.41 mg/mL (~26.63 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 | 2.1459 mL | 10.7294 mL | 21.4588 mL | |
| 5 mM | 0.4292 mL | 2.1459 mL | 4.2918 mL | |
| 10 mM | 0.2146 mL | 1.0729 mL | 2.1459 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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