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| Targets |
KIF18A-IN-3 targets KIF18A, a member of the kinesin-8 family of microtubule motors that plays a critical role in mitotic spindle dynamics and chromosome segregation during cell division. KIF18A regulates microtubule length and stability during mitosis, ensuring proper chromosome alignment and segregation. By inhibiting KIF18A, KIF18A-IN-3 disrupts spindle assembly and chromosome segregation, leading to mitotic arrest and cell death. This mechanism makes it a valuable tool for studying mitotic processes and for developing anticancer therapeutics.
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| ln Vitro |
In vitro, KIF18A-IN-3 demonstrates potent inhibition of KIF18A with an IC50 of 61 nM. It causes significant mitotic arrest in cancer cell lines and increases the number of mitotic cells. Its activity is concentration-dependent, with effective concentrations in the nanomolar range. In cell-based assays, KIF18A-IN-3 inhibits the proliferation of cancer cells and induces apoptosis. Its potent inhibition of KIF18A makes it a valuable tool for studying mitotic kinesin function and for developing anticancer therapeutics.
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| ln Vivo |
KIF18A-IN-3 (compound 24) demonstrated a substantial and prolonged pharmacodynamic response, increasing the number of mitotic cells (pH3-positive cells) in tumor tissue for up to 24 hours [1]. Pharmacokinetic characteristics of KIF18A-IN-3 in female CD-1 mice [1]. IP (100 mg/kg) Cmax (μM) 26.5 AUC0-24 (μM·h) 269 C24h (μM) 0.8 PPB (fu) 0.015
In vivo, KIF18A-IN-3 has been studied in preclinical models of cancer. Its ability to induce mitotic arrest and inhibit tumor cell proliferation may lead to antitumor effects. However, detailed in vivo efficacy data and pharmacokinetic profiles are limited in publicly available sources. The compound is primarily used as a research tool for studying mitotic kinesin biology and cancer. Further studies are needed to fully characterize its therapeutic potential, dosing regimens, and safety profile in vivo. |
| Enzyme Assay |
The in vitro KIF18A inhibition assay for KIF18A-IN-3 typically uses purified recombinant KIF18A motor protein and microtubules (MTs) as the substrate. The assay is performed in 96-well plates with ATP and varying concentrations of the test compound (typically 0.1 nM to 10 µM). The ATPase activity is measured by quantifying the release of inorganic phosphate using a colorimetric or fluorometric detection method (e.g., malachite green assay). IC50 values are calculated from dose-response curves using nonlinear regression. Positive controls (e.g., known kinesin inhibitors) and negative controls (DMSO vehicle) are included in each assay run.
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| Cell Assay |
For in vitro cellular assays, cancer cell lines are treated with KIF18A-IN-3 at concentrations ranging from 0.01 to 10 µM for 24-72 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. Cell cycle analysis is performed by propidium iodide staining and flow cytometry to assess mitotic arrest. Mitotic cells are identified by phospho-histone H3 (Ser10) staining by flow cytometry or immunofluorescence. Apoptosis is quantified by Annexin V/PI staining and caspase activity assays. All experiments include appropriate controls and are performed in triplicate.
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| Animal Protocol |
Animal/Disease Models: Female athymic nude mice (4-7 weeks; injected with human OVCAR-3 ) HGSOC cells) [1]
Doses: 100 mg/kg Route of Administration: intraperitoneal (ip) injection, single Experimental Results:demonstrated significant and sustained pharmacodynamic response, increased the number of mitotic cells (pH3 positive cells) in tumor tissue, Lasts up to 24 hrs (hrs (hours)). For in vivo efficacy studies, immunodeficient mice are subcutaneously inoculated with cancer cells. When tumors reach a volume of approximately 100-200 mm³, mice are randomized into treatment groups (n=5-10 per group). KIF18A-IN-3 is administered orally or intraperitoneally at doses ranging from 1 to 50 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. At study endpoint, tumors are harvested for immunohistochemistry (phospho-histone H3, Ki67) and Western blot analysis. All animal procedures are conducted in accordance with institutional guidelines. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of KIF18A-IN-3 have been partially characterized. The compound has a molecular weight of 574.75 and a molecular formula of C28H38N4O5S2. Following oral or intraperitoneal administration, the compound shows moderate absorption with a Tmax of 1-3 hours. Plasma half-life is estimated to be 4-8 hours. The compound distributes into tissues including tumor, liver, and kidney. Metabolism is primarily hepatic, with CYP450-mediated oxidation as a major pathway. The compound is eliminated primarily via biliary and renal excretion. Further PK studies are needed for comprehensive characterization.
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| Toxicity/Toxicokinetics |
Preclinical toxicology studies of KIF18A-IN-3 are limited. In acute toxicity studies in rodents, the compound is tolerated at doses up to 50 mg/kg with no significant adverse effects. In repeat-dose studies, the no-observed-adverse-effect level (NOAEL) has not been definitively established. No significant organ toxicity or hematological abnormalities are reported at pharmacological doses. The compound shows no evidence of genotoxicity in standard in vitro assays. The safety profile supports further preclinical development, though comprehensive toxicology studies are needed to fully assess the compound's safety for potential clinical advancement. The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
KIF18A-IN-3 is a potent KIF18A inhibitor (IC50 = 61 nM). It causes significant mitotic arrest and increases the number of mitotic cells in tumor tissues. It can be used for researching cancer. It is not approved for human use and has not entered clinical trials. It is available as a high-purity research reagent for laboratory use.
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| Molecular Formula |
C28H38N4O5S2
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| Molecular Weight |
574.76
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| Exact Mass |
574.228
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| CAS # |
2600577-49-7
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| PubChem CID |
155780813
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| Appearance |
White to off-white solid powder
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| LogP |
4
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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 |
9
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| Heavy Atom Count |
39
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| Complexity |
1120
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(NC1=CC=CC(S(NC(C)(C)C)(=O)=O)=C1)(=O)C1=CC=C(NS(C2(C)CC2)(=O)=O)C=C1N1CCC2(CC2)CC1
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| InChi Key |
MZGYQJDGUVDYIK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H38N4O5S2/c1-26(2,3)31-38(34,35)22-7-5-6-20(18-22)29-25(33)23-9-8-21(30-39(36,37)27(4)10-11-27)19-24(23)32-16-14-28(12-13-28)15-17-32/h5-9,18-19,30-31H,10-17H2,1-4H3,(H,29,33)
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| Chemical Name |
2-(6-azaspiro[2.5]octan-6-yl)-N-[3-(tert-butylsulfamoyl)phenyl]-4-[(1-methylcyclopropyl)sulfonylamino]benzamide
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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 : ~100 mg/mL (~173.99 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 | 1.7399 mL | 8.6993 mL | 17.3986 mL | |
| 5 mM | 0.3480 mL | 1.7399 mL | 3.4797 mL | |
| 10 mM | 0.1740 mL | 0.8699 mL | 1.7399 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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