GDC-0623

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Chemical Structure| 1168091-68-6 同义名 : RG 7421;MEK inhibitor 1;GDC-0632;G-868
CAS号 : 1168091-68-6
货号 : A420396
分子式 : C16H14FIN4O3
纯度 : 99%+
分子量 : 456.21
MDL号 : MFCD25976760
存储条件：

Pure form Keep in dark place,Sealed in dry,2-8°C

In solvent -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 50 mg/mL(109.6 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

5% DMSO+45% PEG 300+water 20 mg/mL suspension

生物活性
靶点

  • MEK1

    MEK1, IC50:0.13 nM
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 Ki 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].
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.19mL

0.44mL

0.22mL

10.96mL

2.19mL

1.10mL

21.92mL

4.38mL

2.19mL
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.