GDC-0623
(Synonyms: RG 7421; MEK inhibitor 1) 目录号 : GC14247
A potent, ATP-uncompetitive inhibitor of MEK1
Cas No.:1168091-68-6
Sample solution is provided at 25 µL, 10mM.
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GDC-0623 is a potent and ATP-uncompetitive inhibitor of MEK1 with Ki value of 0.13nM [1].
GDC-0623 is an allosteric MEK inhibitor and has efficacy against both mutant BRAF and mutant KRAS. In the cell viability assays, GDC-0623 inhibits BRAF (V600E) and KRAS (G13D) with EC50 values of 7nM and 42nM, respectively in A375 cells and HCT116 cells. Besides that, GDC-0623 shows similar efficacy in the two genotypes in a panel of BRAF and KRAS-mutant cancer cell lines. GDC-0623 is found to prevent MEK phosphorylation in cells, resulting in more effective inhibition of pERK. Furthermore, it is found that GDC-0623 blocks RAF activation through the effect on MEK. It induces dimerization of MEK with both BRAF and CRAF and stabilizes the RAF–MEK complex. In addition, GDC-0623 also suppresses RAF activation via inhibiting the formation of BRAF–CRAF heterodimer and the translocation of RAF in plasma membrane [1].
References:
[1] Hatzivassiliou G, Haling J R, Chen H, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS-versus BRAF-driven cancers. Nature, 2013, 501(7466): 232-236.
| Kinase experiment [1]: | |
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In vitro Kinase assays |
0.14 μM of purified inactive recombinant MEK-1 protein is preincubated with inhibitors in 15 μL of kinase buffer including (20 mM MOPS pH7.2, 25 mM beta glycerol phosphate, 5 mM EGTA, 1 mM sodium orthovanadate, 1 mM DTT, 100 μM ATP, 15 mM MgCl2). After incubating 10 minutes at 30°C, 1 ng of BRAF, CRAF or BRAF V600E combined with 0.5 μg of inactive recombinant ERK2 is added to the reaction in total volume of 20 μL. After incubating 30 minutes at 30°C the reaction is stopped by adding Laemmle sample buffer. Enzyme activity is measured by determining level of phosphor-MEK by SDS-PAGE. Immunoreactive proteins are visualized with SuperSignal West Pico Chemiluminescent Substrate. |
| Cell experiment [1, 2]: | |
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Cell lines |
KRAS mutant HCT116 or SW620 cells |
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Preparation method |
Soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
0.01-0.15 μmol/L; 3h-48 h; |
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Applications |
GDC-0623 dose- and time-dependently up-regulated the pro-apoptotic BH3-only protein BIM in HCT116 cells or KRAS mutant HCT116 or SW620 cells. GDC-0623 inhibited cellular proliferation with EC50 values of 4 nM, 53 nM, 11 nM, 18 nM and 94 nM for A375 (BRAFV600E), HCT116 (KRASG13D), COLO 205, HT-29, and HCT116 cells, respectively. |
| Animal experiment [1]: | |
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Animal models |
Mice bearing A375, MiaPaCa-2, and HCT116 xenografts |
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Dosage form |
40 mg/kg, oral gavage (PO), by mouth once a day, for 20 days |
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Applications |
GDC-0623 showed tumour growth inhibition of 120% and 115% in MiaPaCa-2 and HCT116 xenografts tumour models, respectively. |
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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. Hatzivassiliou, G., Haling, J. R., Chen, H., Song, K., Price, S., Heald, R., Hewitt, J. F., Zak, M., Peck, A., Orr, C., Merchant, M., Hoeflich, K. P., Chan, J., Luoh, S. M., Anderson, D. J., Ludlam, M. J., Wiesmann, C., Ultsch, M., Friedman, L. S., Malek, S. and Belvin, M. (2013) Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers. Nature. 501, 232-236 2. Zaanan, A., Okamoto, K., Kawakami, H., Khazaie, K., Huang, S. and Sinicrope, F. A. (2015) The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism. J Biol Chem. 290, 23838-23849 |
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| Cas No. | 1168091-68-6 | SDF | |
| 别名 | RG 7421; MEK inhibitor 1 | ||
| 化学名 | 5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide | ||
| Canonical SMILES | C1=CC(=C(C=C1I)F)NC2=C(C=CC3=CN=CN32)C(=O)NOCCO | ||
| 分子式 | C16H14FIN4O3 | 分子量 | 456.21 |
| 溶解度 | ≥ 16.85mg/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 | 2.192 mL | 10.9599 mL | 21.9197 mL |
| 5 mM | 0.4384 mL | 2.192 mL | 4.3839 mL |
| 10 mM | 0.2192 mL | 1.096 mL | 2.192 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: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet