MAPK (RAF/MEK/ ERK) kinase pathway is a validated pathway for cancer therapeutic intervention (e.g. melanoma). Blockade of this pathway is expected to shut down an mTORCi escape mechanism involving activation of MEK pathway signaling. Though some BRAF and MEK inhibitors have been FDA-approved or are at late stage of clinical trials, the resistance to BRAFi and MEKi presents an emerging unmet medical need. ERK is a major signaling convergence point in human cancers. Tumor biology data suggests that targeting ERK hold high potential to overcome or prevent resistance from BRAFi and MEKi. Using structure-based drug design, we discovered CC-90003, which forms covalent bond with the Cys in the ATP binding sites of ERK1/2. The enhanced pharmacodynamimcs effect was demonstrated by prolonged inhibition of p-RSK and extended ERK occupancy recovery after compound washout. CC-90003 inhibited the cell growth against not only a broad spectrum of BRAF- and KRAS-mutant cell lines, but also against vemurafinib- and trametinib-resistant A375R clones and trametinib-resistant HCT116R polyclonal cells. In vivo, tumor growth inhibition results in BRAFV600E (A375, LOX IMVI melanoma) and KRasG13D (HCT116 colon) xenograft models correlated with ERK occupancy in tumor tissues, as presented in QD and QOD dose regimen.

Discovery of CC-90003: A covalent ERK1/2 inhibitor

254th National Meeting (2017)

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