GDC-0994

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

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

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.