Background
GDC-0994 is a potent and selective inhibitor of ERK1/2 with IC50 values of 1.1 and 0.3 nM, respectively [1].
The extracellular-signal-regulated kinases (ERK1 and ERK2) are members of the MAP kinase family and act downstream of the RAS/RAF/MEK/ERK signaling cascade that are commonly activated by upstream oncogenic signaling or oncogenic mutations in BRAF or RAS. ERK1/2 play important roles in proliferation, differentiation and cell cycle progression [1].
GDC-0994 is an orally available and potent ERK1/2 inhibitor with potential antineoplastic activity. In mice bearing KRAS-mutant and BRAF-mutant human xenograft tumors, GDC-0994 exhibited significant single-agent activity and inhibited phospho-p90RSK [1]. When orally administration, GDC-0994 inhibited both activation of ERK-mediated signal transduction pathways and ERK phosphorylation, which then inhibited ERK-dependent tumor cell survival and proliferation.
参考文献:
[1].? Robarge K, Schwarz J, Blake J, et al. Abstract DDT02-03: Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development. AACR Annual Meeting, 2014, San Diego, CA.
Protocol
| Cell experiment [1]: |
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Cell lines
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BRAFV600E cell lines
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Preparation method
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The solubility of this compound in DMSO is >22.1mg/mL. 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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Applications
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In BRAFV600E cell lines, treatment with GDC-0994 resulted in stronger pathway inhibition and subsequent suppression of cell proliferation when compared to BRAF inhibitors.
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| Animal experiment [2]: |
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Animal models
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Mice bearing KRAS-mutant and BRAF-mutant human xenograft tumors, HT29 colorectal cancer xenograft model.
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Dosage form
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Oral administration, daily
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Application
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Daily, oral administration of GDC-0994 resulted in significant single-agent activity in KRAS-mutant and BRAF-mutant human xenograft tumors in mice.
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Other notes
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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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参考文献:
[1]. Nambu T, Iwai K, Shibata S, et al. Identification of driver of anti-tumor activity of TAK-931 in human colorectal cancer xenograft model[J]. European Journal of Cancer, 2016, 69: S30.
[2]. Robarge K, Schwarz J, Blake J, et al. Abstract DDT02-03: Discovery of GDC-0994, a potent and selective ERK1/2 inhibitor in early clinical development. AACR Annual Meeting, 2014, San Diego, CA.
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