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| Targets |
GW406108X targets two distinct proteins: Kif15 (Kinesin-12), a motor protein essential for mitotic spindle assembly, and ULK1 (Unc-51-like autophagy activating kinase 1), a key regulator of autophagy initiation. As a Kif15 inhibitor with an IC50 of 0.82 μM, it disrupts mitotic spindle dynamics. As an ATP-competitive ULK1 inhibitor with a pIC50 of 6.37 (427 nM), it blocks autophagy initiation without affecting upstream mTORC1 and AMPK signaling.
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| ln Vitro |
Monitoring ULK1 pS758 (mTOR site) or pS556 (AMPK site) levels demonstrates that GW406108X operates on ULK1 and autophagy without changing mTOR or AMPK activity. With pIC50 values of 6.34 (457 nM) and 6.38 (417 nM), respectively, GW406108X inhibits both AMPK and VPS34. The presence of 5 μM GW406108X greatly reduces the increase in ATG13 phosphorylation that is caused by hunger [1]. Kif15-N420 ATPase activity is 76% inhibited by GW406108X[2].
In vitro, GW406108X inhibits Kif15 with an IC50 of 0.82 μM in ATPase assays. It inhibits recombinant ULK1 kinase activity with a pIC50 of 6.37 (427 nM). GW406108X blocks autophagy in cells, without affecting upstream signaling kinases mTORC1 and AMPK. At 5 μM, it greatly reduces the increase in ATG13 phosphorylation caused by nutrient starvation, confirming its effect on autophagy initiation. |
| ln Vivo |
In vivo data for GW406108X is not extensively reported in publicly available sources. As a dual inhibitor of Kif15 and ULK1, the compound has potential applications in animal models of cancer and autophagy-related diseases. By inhibiting Kif15, it could disrupt mitotic spindle dynamics and inhibit tumor growth. By inhibiting ULK1, it could modulate autophagy in disease models. However, specific published in vivo efficacy studies are not detailed in the current literature. GW406108X is primarily used as a research tool.
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| Enzyme Assay |
The in vitro Kif15 inhibition assay for GW406108X uses recombinant Kif15 protein and measures ATPase activity in the presence of varying compound concentrations. ATPase activity is detected using colorimetric or luminescent methods, and IC50 values are calculated from dose-response curves. The ULK1 inhibition assay uses recombinant ULK1 kinase and a peptide substrate, with kinase activity measured using radioactive or luminescent detection methods. Autophagy inhibition is confirmed by monitoring LC3-II accumulation and autophagic flux.
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| Cell Assay |
Cellular assays for GW406108X are conducted in various cell lines to study its effects on autophagy and mitosis. Cells are treated with varying concentrations of GW406108X (typically 5 μM). Autophagy is assessed by monitoring LC3-II accumulation and autophagic flux using Western blotting and fluorescence microscopy. ULK1 inhibition is confirmed by measuring ATG13 phosphorylation. Cell cycle analysis is performed by flow cytometry to assess the effects of Kif15 inhibition on mitosis. Cell viability and proliferation are measured using standard assays.
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| Animal Protocol |
In vivo studies for GW406108X would typically involve xenograft mouse models of cancer or animal models of autophagy-related diseases. The compound would be administered via intraperitoneal or oral routes at doses determined by pharmacokinetic studies. Efficacy would be assessed by measuring tumor growth inhibition or disease phenotype improvement. However, specific published in vivo protocols for GW406108X are not available in the current literature. The compound is currently used as a research tool.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for GW406108X is not extensively reported in publicly available sources. The compound has a molecular weight of 400.21 g/mol and a molecular formula of C20H11Cl2NO4. It is soluble in DMSO at 80 mg/mL (199.89 mM) but insoluble in water and ethanol. For oral administration in vivo, it can be formulated as a homogeneous suspension in CMC-Na at ≥5 mg/mL. Storage conditions: powder at -20°C. Detailed PK parameters such as half-life are not available.
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| Toxicity/Toxicokinetics |
Toxicity data for GW406108X is limited in publicly available sources. As with all research compounds, GW406108X is intended for research use only and not for human therapeutic applications. Standard in vitro cytotoxicity assays and in vivo tolerability studies would be required for a complete toxicity assessment. The compound's dual inhibition of Kif15 and ULK1 suggests potential on-target effects that would need to be evaluated.
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| References | |
| Additional Infomation |
GW406108X (GW108X) is a specific Kif15 (Kinesin-12) inhibitor with an IC50 of 0.82 μM. It is also a potent autophagy inhibitor and ATP-competitive inhibitor of ULK1 with a pIC50 of 6.37 (427 nM). GW406108X inhibits ULK1 kinase activity and blocks autophagic flux without affecting upstream mTORC1 and AMPK. At 5 μM, it reduces starvation-induced ATG13 phosphorylation. It has a molecular formula of C20H11Cl2NO4 and a molecular weight of 400.21 g/mol. GW406108X is a valuable tool for studying Kif15 function, autophagy, and mitotic spindle dynamics.
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| Molecular Formula |
C20H11CL2NO4
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|---|---|
| Molecular Weight |
400.211643457413
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| Exact Mass |
399.006
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| CAS # |
1644443-92-4
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| PubChem CID |
44312236
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
4.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
27
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| Complexity |
628
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(=C(C=C(C=1)/C=C1\C(NC2C=CC(C(C3=CC=CO3)=O)=CC=2\1)=O)Cl)O
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| InChi Key |
XKTUKRBLWOHYIL-MLPAPPSSSA-N
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| InChi Code |
InChI=1S/C20H11Cl2NO4/c21-14-7-10(8-15(22)19(14)25)6-13-12-9-11(3-4-16(12)23-20(13)26)18(24)17-2-1-5-27-17/h1-9,25H,(H,23,26)/b13-6-
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| Chemical Name |
(3Z)-3-[(3,5-dichloro-4-hydroxyphenyl)methylidene]-5-(furan-2-carbonyl)-1H-indol-2-one
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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 : 50 mg/mL (124.93 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (5.20 mM) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4987 mL | 12.4934 mL | 24.9869 mL | |
| 5 mM | 0.4997 mL | 2.4987 mL | 4.9974 mL | |
| 10 mM | 0.2499 mL | 1.2493 mL | 2.4987 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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