(S)-Crizotinib |
| カタログ番号GC13136 |
(S)-クリゾチニブは、IC50 が 330 nM の強力かつ選択的な MTH1 (mutT ホモログ) 阻害剤です。 (S)-クリゾチニブは、MTH1 阻害を介してヌクレオチド プールの恒常性を破壊し、DNA 一本鎖切断の増加を誘導し、ヒト結腸癌細胞の DNA 修復を活性化し、動物モデルの腫瘍増殖を効果的に抑制します。
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1374356-45-2
Sample solution is provided at 25 µL, 10mM.
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(S)-crizotinibthe selectively inhibited MTH1 catalytic activity with IC50 of 72 nM, while clinically used (R)-enantiomer of the drug was inactive with IC50 of 1375 nM. Furthermore, direct-binding assays (ITC) indicated a 16-fold higher affinity of the (S)-enantiomer towards MTH1 compared with (R)-enantiomer. By using Km concentrations of substrates, the average IC50 values for (S)-crizotinib and the MTH1 substrates 8-oxo-dGTP and 2-OH-dATP were 330 nM and 408 nM respectively. (S)-crizotinib efficiently inhibited colony formation of SW480 cells andKRAS-mutated PANC1 cells, similar to SCH51344. In addition, in vitro Kd measurements indicated that (S)-crizotinib was considerably less potent than the (R)-enantiomer against the established targets ALK,MET and ROS1. (S)-crizotinib did not lead to the detection of any significant effects on proliferation in SW480 cells and showed highest toxicity towards the SV40T and KRASV12 cells. (S)-crizotinib, in contrast to (R)-crizotinib, efficiently stabilized MTH1 validating the differential targeting within BJ-KRASV12 cells using a cellular thermal shift assay. (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models as a result of disruption of nucleotide pool homeostasis via MTH1 inhibition.
In vivo mouse xenograft studies showed (S)-crizotinib, but not the (R)-enantiomer, was able to impair overall tumour progression aswell as specifically reduce tumour volume by more than 50%.
References:
1. Huber KVM, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. NATURE,2014;508:222-227
| Cell experiment:[1] | |
|
Cell lines |
BJ, H1437, H2122, H23, H358, H460, HCT116 and U2OS cells |
|
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. |
|
Reaction Conditions |
BJ, SV40T, RASV12-cells (5 μM, 3h); U2OS cells (5 μM, 24h) |
|
Applications |
(S)-crizotinibthe selectively inhibited MTH1 catalytic activity with IC50 of 72 nM, while clinically used (R)-enantiomer of the drug was inactive with IC50 of 1375 nM. Furthermore, direct-binding assays (ITC) indicated a 16-fold higher affinity of the (S)-enantiomer towards MTH1 compared with (R)-enantiomer. By using Km concentrations of substrates, the average IC50 values for (S)-crizotinib and the MTH1 substrates 8-oxo-dGTP and 2-OH-dATP were 330 nM and 408 nM respectively. (S)-crizotinib efficiently inhibited colony formation of SW480 cells andKRAS-mutated PANC1 cells, similar to SCH51344. In addition, in vitro Kd measurements indicated that (S)-crizotinib was considerably less potent than the (R)-enantiomer against the established targets ALK,MET and ROS1. (S)-crizotinib did not lead to the detection of any significant effects on proliferation in SW480 cells and showed highest toxicity towards the SV40T and KRASV12 cells. (S)-crizotinib, in contrast to (R)-crizotinib, efficiently stabilized MTH1 validating the differential targeting within BJ-KRASV12 cells using a cellular thermal shift assay. (S)-crizotinib induced an increase in DNA single-strand breaks, activated DNA repair in human colon carcinoma cells, and effectively suppressed tumour growth in animal models as a result of disruption of nucleotide pool homeostasis via MTH1 inhibition. |
| Animal experiment:[2] | |
|
Animal models |
SCID mice (female, 5–6 weeks) |
|
Dosage form |
25 mg per kg,subcutaneously daily; 50 mg per kg, orally, daily |
|
Applications |
In vivo mouse xenograft studies showed (S)-crizotinib, but not the (R)-enantiomer, was able to impair overall tumour progression aswell as specifically reduce tumour volume by more than 50%. |
|
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. |
|
References: 1. Huber KVM, Salah E, Radic B, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. NATURE,2014;508:222-227 | |
| Cas No. | 1374356-45-2 | SDF | |
| Chemical Name | 3-[(1S)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4-yl)pyridin-2-amine | ||
| Canonical SMILES | CC(C1=C(C=CC(=C1Cl)F)Cl)OC2=C(N=CC(=C2)C3=CN(N=C3)C4CCNCC4)N | ||
| Formula | C21H22Cl2FN5O | M.Wt | 450.34 |
| 溶解度 | ≥ 33.3mg/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. |
||
| 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 | 2.2205 mL | 11.1027 mL | 22.2054 mL |
| 5 mM | 0.4441 mL | 2.2205 mL | 4.4411 mL |
| 10 mM | 0.2221 mL | 1.1103 mL | 2.2205 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: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 8 reference(s) in Google Scholar.)
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