COMMENT SCH772984 is an extremely selective ERK1/2 inhibitor and effectively suppresses MAPK pathway signaling and cell proliferation in BRAF, MEK, and BRAF​/MEK inhibitor-​resistant tumor models. In vitro resistance has been observed due to a mutation of glycine to aspartic acid (G186D) in the DFG motif of ERK1. SCH772984 induces an unusual binding pocket which is created by an inactive conformation of the phosphate-​binding loop and a shift of the α-C helix. Jun 16 2016 - 5:32pm; SCH772984 inhibits ERK protein kinase with a nanomolar IC50 in vitro (1 nM for ERK2, and 4 nM for ERK4) while being much less potent against MEK1 (IC50 >10 uM). At 1 uM, this probe also inhibits the following kinases: CLK2 (65%), FLT4 (VEGFR3) 60%, GSG2 (Haspin) 51%, MAP4K4 (HGK) 71%, MAPK1 (ERK2) 100%, MINK1 66%, PRKD1 (PKC mu) 50%, TTK* 62%. In contrast to other reported ERK inhibitors (VTX-11e), this inhibitor also inhibits activating phosphorylation of ERK by MEK kinase at 100 nM, and inhibits phosphorylation of ERK downstream substrate pRSK. Prolonged inhibition of ERK with this inhibitor (36 h; 2 uM) leads to the inhibition of C-RAF phosphorylation (S289; S296; S301) by ERK (Mol. Cell 2005; 17; 215-24). This activates C-RAF leading to the increased phosphorylation of ERK. However, even with the increase in ERK phosphorylation, this inhibitor maintains the inhibition of the downstream ERK substrate, pRSK. Furthermore, the compound was active against cancer cells that were resistant against a combination of B-RAF and MEK inhibitors. SCH772984 successfully inhibited ERK and RSK phosphorylation at 2 uM, while a combination of 10 uM PLX4032 (BRAF-inhibitor) and 1 uM Trametinib (MEK inhibitor) was not able to inhibit ERK and RSK phosphorylation in the same cells. Jun 29 2016 - 7:57pm; SCH772984 is a potent inhibitor of ERK1 and ERK2, with very high selectivity over other kinases, especially when used at concentrations below 1 micromolar. Strong on-target inhibition of ERK signalling (pRSK) and inhibition of ERK activation (pERK) in cellular assays has been demonstrated from concentrations of 100 nanomolar. The unusual protein kinase conformation induced by SCH772984 is associated with slow binding kinetics in vitro and in cell-based systems (see doi: 10.1038/nchembio.1629). SCH779824 is tolerated for in vivo use by intraperitoneal injection (12.5 - 50 mg/kg, twice daily dosing). Target inhibition in vivo is seen, with strong inhibition of ERK activation (pERK, measured 6 h after last dose) in LOX (BRAF-mutant melanoma) human tumor xenografts treated with SCH779824 (12.5 mg/kg i.p). Aug 25 2016 - 11:40am

DESCRIPTION SCH772984 is an experimental inhibitor of the mitogen-activated protein kinases ERK1 and ERK2 . The in vitro mechanism of action of SCH772984 is notable, in that it inhibits both the catalytic activity of ERK1/2 and also inhibits phosphorylation of ERK1/2. This is in contrast to other ERK inhibitors that target the ATP-binding site and thus inhibit only the catalytic activity of the kinases. The dual action of compounds like SCH772984 is predicted to block the nuclear localization of pERK and more completely suppress MAPK pathway signaling . This type of inhibitor may provide improved clinical efficacy, particularly in relation to the emergence of acquired resistance that occurs in BRAF and MEK inhibitor-treated cancers. Unfortunately, SCH772984 is not active in vivo (oral or intraperitoneal administration results in poor exposure levels) . (GtoPdb)

DESCRIPTION SCH772984 is an investigational inhibitor of the mitogen-activated protein kinases ERK1 and ERK2 .

MOA ATP-competitive inhibitor (Chemical Probes.org)