生物活性

• 靶点

  ERK1 IC50:1.1nM

  ERK2 IC50:0.3nM

• 描述ERK1/2 (extracellular-signal-regulated kinases) is only known substrates of the MEK1/2 as well as the essential node in RAS/RAF/MEK/ERK signaling cascade, which can be activated by catalyzing the phosphorylation on T202/Y204 through MEK1/2. GDC-0994 is a selective inhibitor of ERK1/2 with IC₅₀ value of 6.1nM and 3.1nM (measured by enzyme potency), respectively. Cellular study showed that GDC-0994 could inhibit ERK dependent p-RSK with IC50 value of 12nM in PMA-stimulated HepG2 cells^[1]. Distinguished with the other published ERK inhibitors, GDC-0994 did not change the level of p-ERK, suggesting the alternative mechanisms of action with respect to feedback signaling of it^[2]. The inhibition of p-RSK in these tumors correlating with potency in vitro and in vivo may be the pharmacodynamics biomarker. Oral administration with GDC-0994 once daily for 21 days caused significant tumor growth inhibition by 49%, 57% and 80% at dose of 30, 60 and 100mg/kg in nude mice bearing HCT116 xenograft tumors^[1].
• 作用机制Not found

• 动物研究
  剂量	Mice: 60 mg/kg[2] (p.o.)
  给药途径	p.o.

• 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
  NCT02457793	Non-Small Cell Lung Cancer, Me... more >>tastatic Colorectal Cancer, Metastatic Non Small Cell Lung Cancer, Metastatic Cancers, Melanoma Collapse <<	Phase 1	Completed	-	United States, Colorado ... more >> University of Colorado Aurora, Colorado, United States, 80045-2517 United States, Connecticut Yale Cancer Center New Haven, Connecticut, United States, 06520 United States, Massachusetts Dana Farber Cancer Institute Boston, Massachusetts, United States, 02215 United States, Missouri Washington University School of Medicine Saint Louis, Missouri, United States, 63110 United States, Tennessee Sarah Cannon Research Institute Nashville, Tennessee, United States, 37203 Collapse <<
  NCT01875705	Solid Tumor	Phase 1	Completed	-	United States, Connecticut ... more >> Yale Cancer Center; Medical Oncology New Haven, Connecticut, United States, 06520 United States, Michigan Karmanos Can Inst Detroit, Michigan, United States, 48201 United States, Tennessee Sarah Cannon Research Inst. Nashville, Tennessee, United States, 37203 France Institut Gustave Roussy; Departement Oncologie Medicale Villejuif, France, 94805 Collapse <<
  NCT02457793	-	-	Completed	-	-

• 参考文献

• [1] Blake JF, Burkard M, et al. Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development. J Med Chem. 2016 Jun 23;59(12):5650-60.