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| Targets |
CSF1R (IC50 = 2 nM); VEGFR2 (IC50 = 12 nM); c-Kit (IC50 = 451 nM); PDGFRβ (IC50 = 217 nM)
The primary target of KI-20227 is c-Fms tyrosine kinase (CSF1R/M-CSFR). KI-20227 is a potent and orally bioavailable inhibitor of c-Fms tyrosine kinase with an IC50 of 2 nM. It also shows inhibitory activity against VEGFR-2 (IC50: 12 nM), c-Kit (IC50: 451 nM), and PDGFRβ (IC50: 217 nM). CSF1R is a receptor tyrosine kinase that plays a critical role in the survival, proliferation, and differentiation of macrophages and osteoclasts. By inhibiting CSF1R, KI-20227 can prevent osteoclast differentiation and osteolytic destruction. |
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| ln Vitro |
Ki20227 is a novel quinoline-urea derivative that inhibits the tyrosine kinase of c-Fms. It is discovered that Ki20227 has inhibitory concentrations of 2, 12, 451, and 217 nmol/L for c-Fms, vascular endothelial growth factor receptor-2 (KDR), stem cell factor receptor (c-Kit), and platelet-derived growth factor receptor B, respectively. Moreover, Ki20227 has been shown to suppress M-CSF-dependent M-NFS-60 cell growth in vitro, but not M-CSF-independent A375 human melanoma cell growth. Moreover, Ki20227 dose-dependently suppresses the growth of tartrate-resistant acid phosphatase-positive osteoclast-like cells in an osteoclast-like cell formation assay employing mouse bone marrow cells.[1]
KI-20227 inhibits c-Fms tyrosine kinase with an IC50 of 2 nM. It also shows inhibitory activity against VEGFR-2 (IC50: 12 nM), c-Kit (IC50: 451 nM), and PDGFRβ (IC50: 217 nM). The compound prevents osteoclast differentiation and osteolytic destruction. Its potent inhibition of CSF1R makes it a valuable tool for studying macrophage and osteoclast biology. The compound's activity against VEGFR-2 may contribute to anti-angiogenic effects. |
| ln Vivo |
In vivo experiments using nude rats administering oral Ki20227 after intracardiac injection of A375 cells show suppression of osteoclast-like cell accumulation and bone resorption caused by metastatic tumor cells. Furthermore, in rats that have had their ovaries removed, Ki20227 reduces the quantity of osteoclast-like cells that are acid phosphatase-positive and resistant to tartrate on the surfaces of their bones. The results of this study indicate that Ki20227 suppresses osteoclast accumulation in vivo caused by M-CSF, thereby inhibiting osteolytic bone destruction.[1]
KI-20227 is orally active and prevents osteoclast differentiation and osteolytic destruction. As a CSF1R inhibitor, it would be expected to have effects on macrophage and osteoclast function in vivo. The compound's oral bioavailability makes it suitable for in vivo studies. Its ability to prevent osteolytic destruction suggests potential applications in treating bone diseases such as osteoporosis and cancer bone metastases. However, specific in vivo studies have not been detailed in the available literature. |
| Enzyme Assay |
No specific non-cell assay protocol is available for KI-20227. For kinase inhibitors, standard cell-free assays use recombinant kinase enzymes and peptide substrates. The compound is incubated with the enzyme and substrate, and kinase activity is measured by phosphorylation of the substrate using radioactive ATP or fluorescent detection methods. These assays provide quantitative data on the compound's potency (IC50) against various kinases. Selectivity profiling against a panel of kinases can be performed to assess the compound's specificity.
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| Cell Assay |
The 96-well culture plate is seeded with M-NFS-60, HUVEC, and A375 cells, which are then cultured for a full day. Following this, culture media are swapped out and left to incubate for an additional 72 hours, either with or without Ki20227 (0.1–3,000 nmol/L).
For 12 hours, RAW264.7 cells are serum starved in DMEM with 0.1% FCS. The cells are then treated with serial dilutions of Ki20227 and allowed to incubate for an hour. AVC 264. For four minutes, seven cells are stimulated with 50 ng/mL of recombinant mouse M-CSF. The RAW264 protein contains c-Fms. An ice-cold lysis buffer is used to prepare the 7 cell lysate. No specific cell-based assay protocol is available for KI-20227. For CSF1R inhibitors, standard cellular assays use cells expressing CSF1R or macrophages. Cells are treated with KI-20227 in the presence of CSF-1 (the ligand for CSF1R). CSF1R autophosphorylation and downstream signaling (e.g., ERK, AKT) are measured by western blot. Cell proliferation, survival, and differentiation assays can be performed to assess functional effects. Osteoclast differentiation assays using bone marrow-derived macrophages can assess the compound's effects on osteoclastogenesis. |
| Animal Protocol |
Athymic rats (F344/NJcl-rnu), Sprague-Dawley rats
20 mg/kg Oral gavage No specific animal protocol is available for KI-20227. For studying osteolytic destruction, standard in vivo models include ovariectomy-induced osteoporosis in mice or cancer bone metastasis models. KI-20227 is administered orally for 2-4 weeks. Bone mineral density, bone volume, and osteoclast numbers are assessed by micro-CT and histology. For macrophage studies, models of inflammation or tumor growth may be used. The compound's effects on macrophage infiltration and tumor progression can be evaluated. |
| ADME/Pharmacokinetics |
No detailed pharmacokinetic data is publicly available for KI-20227. The compound has a molecular weight of 480.54 and formula C24H24N4O5S. It is orally bioavailable, indicating favorable absorption properties. The compound is a quinoline-urea derivative with moderate lipophilicity. Comprehensive pharmacokinetic studies would be required to determine absorption, distribution, metabolism, and excretion parameters.
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| Toxicity/Toxicokinetics |
No detailed toxicology data is publicly available for KI-20227. As a research compound, standard preclinical toxicology would be required for therapeutic development. The compound's inhibition of multiple kinases (CSF1R, VEGFR-2, c-Kit, PDGFRβ) suggests potential for both therapeutic effects and side effects related to inhibition of these pathways. The compound is for research use only and not for therapeutic applications.
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| References | |
| Additional Infomation |
KI-20227 has the molecular formula C24H24N4O5S and molecular weight 480.54. The chemical name is N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]-2-methoxyphenyl]-N'-[1-(1,3-thiazole-2-yl)ethyl]urea. It is a quinoline-urea derivative and a potent c-Fms tyrosine kinase inhibitor with an IC50 of 2 nM. It also inhibits VEGFR-2 (IC50: 12 nM), c-Kit (IC50: 451 nM), and PDGFRβ (IC50: 217 nM). The compound prevents osteoclast differentiation and osteolytic destruction. No clinical trial status has been identified.
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| Molecular Formula |
C24H24N4O5S
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|---|---|
| Molecular Weight |
480.539
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| Exact Mass |
480.146
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| Elemental Analysis |
C, 59.99; H, 5.03; N, 11.66; O, 16.65; S, 6.67
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| CAS # |
623142-96-1
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| Related CAS # |
623142-96-1
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| PubChem CID |
9869779
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| Appearance |
Off-white to pink solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
621.8±55.0 °C at 760 mmHg
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| Flash Point |
329.8±31.5 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.651
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| LogP |
4.18
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
34
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| Complexity |
661
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C([H])=C([H])N=C1C([H])(C([H])([H])[H])N([H])C(N([H])C1C([H])=C([H])C(=C([H])C=1OC([H])([H])[H])OC1C([H])=C([H])N=C2C([H])=C(C(=C([H])C=12)OC([H])([H])[H])OC([H])([H])[H])=O
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| InChi Key |
SHPFDGWALWEPGS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H24N4O5S/c1-14(23-26-9-10-34-23)27-24(29)28-17-6-5-15(11-20(17)30-2)33-19-7-8-25-18-13-22(32-4)21(31-3)12-16(18)19/h5-14H,1-4H3,(H2,27,28,29)
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| Chemical Name |
1-[4-(6,7-dimethoxyquinolin-4-yl)oxy-2-methoxyphenyl]-3-[1-(1,3-thiazol-2-yl)ethyl]urea
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| Synonyms |
KI20227; KI-20227; KI 20227
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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: 62.5~96 mg/mL (130.1~199.8 mM)
Water: ˂1 mg/mL Ethanol: ~3 mg/mL (~6.2 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (4.52 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 21.7 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: ≥ 2.17 mg/mL (4.52 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 21.7 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: ≥ 2.17 mg/mL (4.52 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 | 2.0810 mL | 10.4050 mL | 20.8099 mL | |
| 5 mM | 0.4162 mL | 2.0810 mL | 4.1620 mL | |
| 10 mM | 0.2081 mL | 1.0405 mL | 2.0810 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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