(S)-Crizotinib
目录号 : GC13136
An MTH1 inhibitor
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] | |
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Cell lines |
BJ, H1437, H2122, H23, H358, H460, HCT116 and U2OS 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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Reaction Conditions |
BJ, SV40T, RASV12-cells (5 μM, 3h); U2OS cells (5 μM, 24h) |
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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] | |
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Animal models |
SCID mice (female, 5–6 weeks) |
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Dosage form |
25 mg per kg,subcutaneously daily; 50 mg per kg, orally, daily |
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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. |
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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 | |
| 化学名 | 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 | ||
| 分子式 | C21H22Cl2FN5O | 分子量 | 450.34 |
| 溶解度 | ≥ 33.3mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet