1621999-82-3

CC-90003 potently inhibited the kinase activities of ERK1 and ERK2 in biochemical assays, cellular assays and mass spectrometry analysis of 347 kinases with IC50 at 10-20 nM quality, with Good kinase selectivity. In a kinase library containing 258 kinases, it has less than 50% inhibition on 213 kinases, moderate inhibitory activity (50%-80% inhibition) on 28 kinases, and significant inhibitory activity on 17 kinases Inhibition (>80%). Kinase screen in melanoma cell line A375 cells with BRAF V600E mutation, only 5 of 194 kinases (ERK1, ERK2, MKK4, MKK6 and FAK) were significantly inhibited (>80%) by 1 mM CC-90003 . However, the same concentration had no significant inhibitory activity (<14%) on 40 non-kinase enzymes and receptors. By iterative analysis, in cells, in addition to ERK1/2, only three kinases were inhibited by it at biologically relevant concentrations: KDR, FLT3 and PDGFRa. Tumor cells with BRAF mutations are particularly sensitive to it. In most, but not all, cases, it was toxic to KRAS-mutated PDAC, lung and colon cancer cell lines. It did not significantly inhibit the proliferation of normal lung fibroblasts or airway epithelial cells.

In the HCT-116 xenograft in vivo model, CC-90003 was well tolerated within a range (12.5 mg bid-100 mg qd), while 50 mpk bid and 75 mpk bid induced elicited in animals on days 6-18 of dosing die. Both once-daily and twice-daily dosing frequencies resulted in inhibition of tumor growth. It has antitumor activity in all three KRAS-mutated human xenograft models tested.