ChemicalBook Product Catalog Biochemical Engineering Biochemical Reagents Agonist Inhibitors GDC-0994

GDC-0994

Product NameGDC-0994
CAS1453848-26-4
MFC21H18ClFN6O2
MW440.86
EINECS
MOL File1453848-26-4.mol

Chemical Properties

Boiling point	734.6±70.0 °C(Predicted)
Density	1.45±0.1 g/cm3(Predicted)
storage temp.	Store at -20°C
solubility	≥44.1 mg/mL in DMSO; insoluble in H2O; ≥19.2 mg/mL in EtOH
form	solid
pka	14.03±0.10(Predicted)
color	White to yellow
InChIKey	RZUOCXOYPYGSKL-GOSISDBHSA-N
SMILES	C1(=O)N([C@@H](C2=CC=C(Cl)C(F)=C2)CO)C=CC(C2C=CN=C(NC3N(C)N=CC=3)N=2)=C1

Safety Information

HS Code

2933998090

Usage And Synthesis

Description

GDC-0994 is a potent and selective ERK1 and ERK2 inhibitor with IC₅₀ values of 6.1 and 4.1 nM, respectively. It inhibits ERK-dependent p90RSK serine 380 phosphorylation in PMA-stimulated HepG2 cells with an IC₅₀ value of 12 nM. GDC-0994 inhibited growth of HCT116 human colorectal cancer xenograft tumors by 49%, 57%, and 80% at 30, 60, and 100 mg/kg, respectively, when administered orally once daily for 21 days.

Uses

GDC-0994 is a potent and orally available ERK12 inhibitor shown to prevent ERK-dependant tumor cell proliferation and survival.

Synthesis

2(1H)-Pyridinone, 1-[(1S)-1-(4-chloro-3-fluorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-4-[2-[(1-methyl-1H-pyrazol-5-yl)amino]-4-pyrimidinyl]-

1453854-96-0

1453848-26-4

Step B: Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (48 mg) was dissolved in ethyl acetate (4 mL). A solution of ethyl acetate (1.0 mL) saturated with HCl gas was added slowly and dropwise over 2 min. The reaction mixture was stirred at room temperature for 15 min and LCMS analysis showed complete consumption of the raw material. The reaction mixture was concentrated to give an oily residue, which was purified by preparative reversed-phase high-performance liquid chromatography (RP-HPLC) to afford (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 (20.8 mg, 54.6% yield 1H), 7.14 (dd, J = 10.7, 5.1 Hz, 2H), 6.86 (dd, J = 7.3, 1.8 Hz, 1H), 6.27 (d, J = 1.7 Hz, 1H), 5.97 (dd, J = 7.7, 5.7 Hz, 1H), 5.31 (t, J = 5.2 Hz, 1H), 4.15 (m, 1H), 4.10 -3.95 (m, 1H), 3.69 (s, 3H); LCMS m/z 441 (M + H)+.

in vivo

In CD-1 mice, a 10 mg/kg oral dose of Ravoxertinib (GDC-0994) is sufficient to achieve the desired target coverage for at least 8 h^[1]. Daily, oral dosing of Ravoxertinib results in significant single-agent activity in multiple in vivo cancer models, including KRAS-mutant and BRAF-mutant human xenograft tumors in mice^[2].

IC 50

ERK2: 3.1 nM (IC₅₀); ERK1: 6.1 nM (IC₅₀); p-RSK: 12 nM (IC₅₀)

References

[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.

GDC-0994

Chemical Properties

Safety Information

Usage And Synthesis

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