LDC1267 |
| Catalog No.GC14241 |
TAM kinase inhibitor,highly selective
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1361030-48-9
Sample solution is provided at 25 µL, 10mM.
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LDC1267 is a highly selective TAM kinase inhibitor with IC50 of < 5 nM, 8 nM, and 29 nM for Mer, Tyro3, and Axl, respectively.
LDC1267 preferentially inhibits Tyro3, Axl and Mer at low nano-molarity by tracer-based binding assays. Treatment of NKG2D- activated NK cells with LDC1267 indeed abolished the inhibitory effects of Gas6 stimulation; LDC1267 had no apparent additional effect in Cbl-b-deficient NK cells. Adoptive transfer of LDC1267-treated wild-type NK cells significantly increased the anti-tumour response to levels observed in mice transplanted with Cbl-b2/2 NK cells, but did not increase the anti-metastatic efficacy of Cbl-b-knockout NK cells, reinforcing the notion that Cbl-b acts downstream of TAM receptors for NK cell inhibition. [1]
In vivo, wild-type mice treated with LDC1267 showed enhanced cytotoxicity towards RMA cells overexpressing the NKG2D ligand Rae-1 (RMA-Rae1) to the same extent as C373AKI/KI mice, but had no effect on the already enhanced NK cytotoxicity in Cbl-b-mutant mice. LDC1267 markedly reduced metastatic spreading of melanomas; NK1.1 depletion abolished the therapeutic benefits of LDC1267. LDC1267 treatment significantly reduced the numbers and sizes of 4T1 micro-metastases in the liver, without any apparent effect on the primary vehicle LDC1267 mammary tumor. NK cell depletion using anti-asialoGM1 antibodies resulted in markedly enhanced 4T1 liver metastases and abolished the therapeutic benefits of LDC1267. Oral LDC1267 significantly reduced 4T1 liver micro-metastases. [1]
References:
[1]. Paolino M, Choidas A2, Wallner S et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. doi: 10.1038/nature12998. Epub 2014 Feb 19.
| Kinase experiment [1]: | |
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Kinase binding assays |
For optimization of Axl/TAM receptor inhibitors, an Axl binding assay was established (HTRF method; Kinase tracer 236). This assay was based on the binding and displacement of the Alexa Fluor 647-labelled Kinase tracer 236 to each glutathione S-transferase (GST)-tagged kinase used in the binding assay. Binding of the tracer to the kinase was detected by using europium (Eu)-labelled anti-GST antibodies. Simultaneous binding of both the fluorescent tracer and the Eu-labelled antibodies to the GST-tagged kinase generated a fluorescence resonance energy transfer (FRET) signal. Binding of inhibitor to the kinase competed for binding with the tracer, resulting in a loss of the FRET signal. For the assay, the compound was diluted in 20 mM HEPES, pH 8.0, 1 mM DTT, 10 mM MgCl2 and 0.01% Brij35. Then, the kinase of interest (5 nM final concentration), fluorescent tracer (15 nM final concentration) and LanthaScreen Eu-anti-GST antibody (2 nM final concentration) were mixed with the respective compound dilutions (from 5 nM to 10 μM) and incubated for 1 hr. The FRET signal was quantified using an EnVision Multilabellreader 2104. |
| Cell experiment [1]: | |
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Cell lines |
93 cancer cell lines and 2 primary cells (i.e. IMR90 and human peripheral blood mononuclear cells) |
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Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below - 20 °C for several months. |
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Reacting condition |
0 ~ 35 μM; 72 hrs |
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Applications |
In 11 of 95 selected cell lines, LDC1267 moderately affected cell proliferation with the IC50 values of > 5 μM. In NKG2D-activated NK cells, LDC1267 abolished the inhibitory effects on cell proliferation and IFN-γ production induced by Gas6 stimulation. |
| Animal experiment [1]: | |
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Animal models |
Mice bearing B16F10 metastatic melanomas |
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Dosage form |
20 mg/kg; i.p. |
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Applications |
In mice bearing B16F10 metastatic melanomas, LDC1267 efficiently increased anti-metastatic NK cell activity, and inhibited tumor metastases without severe cytotoxicity. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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References: [1]. Paolino M, Choidas A2, Wallner S et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature. 2014 Mar 27;507(7493):508-12. | |
| Cas No. | 1361030-48-9 | SDF | |
| Chemical Name | N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluoro-2-methylphenyl)-1H-pyrazole-3-carboxamide | ||
| Canonical SMILES | FC1=CC=C(N2C=C(OCC)C(C(NC3=CC=C(OC4=CC=NC5=CC(OC)=C(OC)C=C45)C(F)=C3)=O)=N2)C(C)=C1 | ||
| Formula | C30H26F2N4O5 | M.Wt | 560.55 |
| Solubility | ≥ 20.75mg/mL in DMSO | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
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| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.784 mL | 8.9198 mL | 17.8396 mL |
| 5 mM | 0.3568 mL | 1.784 mL | 3.5679 mL |
| 10 mM | 0.1784 mL | 0.892 mL | 1.784 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
Step 2: Enter the in vivo formulation (This is only the calculator, not formulation. Please contact us first if there is no in vivo formulation at the solubility Section.)
Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 40 reference(s) in Google Scholar.)
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