ERK1 (Extracellular Signal-Regulated Kinase 1) and ERK2 belong to the MAP kinase family. ERK1 and ERK2 are the 2 ERKs which play an important role in the MAPK/ERK cascade. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements[2].
LY3214996 is a selective inhibitor of ERK1 and ERK2, with IC50 of 5 nM for both enzymes in biochemical assays. LY3214996 inhibits cellular phospho-RSK1 in BRAF and RAS mutant cancer cell lines. Anti-tumor activity of LY3214996 was observed in tumor cells with MAPK pathway alterations including BRAF, NRAS or KRAS mutation[1]. Another report suggested that LY3214996 may be effective against patient derived RAS-mutant NSCLC cell lines[3].
In tumor xenograft models, LY3214996 inhibits pharmadynamic biomarker phospho-p90RSK1 in tumors. LY3214996 shows either similar or superior anti-tumor activity as compared to other published ERK inhibitors in BRAF or RAS mutant cell lines and xenograft models. Oral administration of single-agent LY3214996 significantly inhibits tumor growth in vivo and is well tolerated in BRAF or NRAS mutant melanoma, BRAF or KRAS mutant colorectal, lung and pancreatic cancer xenografts or PDX models[1].
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