SCH772984 HCl

SCH772984 HCl is a specific inhibitor of extracellular signal-regulated kinase 1/2 (ERK1/2), with IC50 values of 4 nM and 1 nM, respectively [1].

ERK1/2 is a mitogen-activated protein kinase (MAPK) which is involved in the development of various cancers, especially the ones with BRAF or RAS mutations. Phospho-ERK reactivation in cancer cells is associated with resistance to BRAF and MEK inhibitors [1].

In BRAF^V600E-mutant human melanoma cell line LOXIMV1 (LOX), SCH772984 at 0 ~ 300 nM inhibited phosphorylation of the ERK substrate p90 ribosomal S6 kinase in a dose-dependent manner. SCH772984 also reduced phosphorylation of residues in the activation loop of ERK itself. In addition, for approximately 88% and 49% of BRAF-mutant or RAS-mutant tumor lines, SCH772984 exhibited antiproliferative activity with EC50 values < 500 nM. SCH772984 effectively inhibited MAPK signaling and cell proliferation even in tumor cells resistant to concurrent treatment with BRAF and MAP-ERK kinase (MEK) inhibitors [1].

In female nude mice bearing human LOX BRAF^V600E tumors, SCH772984 (12.5, 25, 50 mg/kg, i.p., b.i.d., for 14 days) induced tumor regressions in a dose-dependent manner, and 98% tumor regression was achieved at the largest dose [1].

Reference:

[1]. Morris E J, Jha S, Restaino C R, et al. Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discovery, 2013, 3(7): 742-750.