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CAS No.: 1168091-68-6

GDC-0623 Catalog No. CSN16307

Synonyms: RG 7421;MEK inhibitor 1;G-868

GDC-0623 is a selective and ATP-uncompetitive MEK1 inhibitor with Ki value of 0.13 nM.

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技术信息

生物活性

描述The MAPK/ERK (mitogen-activated protein kinase/extracellular signal-regulated kinase) kinase (MEK) signalling cascade is a key regulator of cellular proliferation, differentiation and survival downstream of RAS activation. Upregulation of this pathway occurs in a large fraction of tumours. GDC-0623 is a potent, ATP-uncompetitive inhibitor of MEK1 with K_i value of 0.13 nM^[3]. GDC-0623 up-regulated BIM (Bcl-2 Interacting Mediator of cell death) expression to a greater extent versus other MEK inhibitors in isogenic KRAS HCT116 and mutant KRAS SW620 colon cancer cells^[1]. In KRAS-mutant cells, block of pMEK (phosphorylated MEK) accumulation caused by GDC-0623 (range: 0.00045–0.33 μM in threefold increments) resulted in more effective inhibition of pERK. MEK phosphorylation was blocked by CRAF and BRAF (V600E) in vitro in the presence of 0.01, 0.1 and 1 μM GDC-0623. In KRAS-mutant cells GDC-0623 at 0.1, 1 and 10 μM induced dimerization of MEK with both BRAF and CRAF. The average plasma concentration of GDC-0973 over 24 hours at its maximum tolerated dose (MTD) is 0.63 μM for GDC-0623. In KRAS-mutant xenograft model, superior antitumour activity was observed with GDC-0623 at its MTD^[3].
作用机制GDC-0623 forms a strong hydrogen-bond interaction with S212 in MEK^[3].
临床研究

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01106599	Solid Cancers	Phase 1	Completed	-	United States, California ... more >> Los Angeles, California, United States, 90033 Sacramento, California, United States, 95817 United States, Oklahoma Oklahoma City, Oklahoma, United States, 73104 United States, Tennessee Nashville, Tennessee, United States, 37203 Collapse <<

参考文献

[1] Zaanan A, Okamoto K, Kawakami H, Khazaie K, Huang S, Sinicrope FA. 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. 2015;290(39):23838-23849.
[2] Zaanan A, Okamoto K, et al. 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. 2015 Sep 25;290(39):23838-49.
[3] Hatzivassiliou G, Haling JR, Chen H, et al. Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers [published correction appears in Nature. 2013 Oct 10;502(7470):258]. Nature. 2013;501(7466):232-236.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.1920 mL
- 10.9599 mL
- 21.9197 mL
- 5 mM
- 0.4384 mL
- 2.1920 mL
- 4.3839 mL
- 10 mM
- 0.2192 mL
- 1.0960 mL
- 2.1920 mL

技术信息

CAS号

1168091-68-6

储存条件

粉末: Keep in dark place,Sealed in dry,2-8°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C16H14FIN4O3

运输

蓝冰

分子量

456.21

别名

RG 7421;MEK inhibitor 1;G-868;GDC-0632

溶解度

DMSO	170.0 mg/mL (372.6 mM)
Water	insoluble

动物实验配方

5% DMSO+45% PEG 300+water

20 mg/mL

suspension

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GDC-0623 Catalog No. CSN16307

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