CC-90003 is an irreversible inhibitor of ERK1/2 with IC50s in the 10-20 nM range and shows good kinase selectivity in a 258-kinase biochemical assay.
In biochemical, cellular, and mass spectrometry assays of 347 kinases, CC-90003 was found to strongly inhibit kinase activities of ERK1 and ERK2 with IC50s in the 10 to 20 nmol/L range and had good kinase selectivity. In a 258-kinase biochemical assay panel, significant inhibition of 213 kinases (<50% inhibition), moderate inhibition of 28 kinases (50%–80% inhibition), and >80% inhibition of 17 kinases by CC-90003 were found. In an ActivX cellular kinase screening using A375 BRAF V600E-mutant melanoma cell line, only 5 of 194 kinases (ERK1, ERK2, MKK4, MKK6, and FAK) were inhibited by >80% at 1 mmol/L of CC-90003. At the same concentration, no significant inhibition (<14%) was found in a Cerep panel of 40 nonkinase enzymes and receptors. Through our iterative analyses, only 3 kinases, in addition to ERK1/2, were inhibited in cells at biologically relevant concentrations: KDR, FLT3, and PDGFRa. Tumors with BRAF mutations were particularly sensitive to CC-90003. In many, but not all cases, CC-90003 had cytotoxic effects in KRAS-mutant PDAC, lung cancer, and colorectal cancer cell lines. CC-90003 does not significantly inhibit proliferation of normal lung fibroblasts or bronchial epithelial cells[1].
In in vivo studies of an HCT-116 xenograft model, CC-90003 was well tolerated at a range of doses (12.5 mg b.i.d.-100 mg qd), although doses of 50 mpk b.i.d. and 75 mpk b.i.d. group caused mortality by days 6 to 18 of study. Both dosing schedules (qd and b.i.d.) leads to tumor growth inhibition. CC-90003 inhibits tumor growth in vivo of three KRAS-mutant PDX models[1].
[1] Aronchik I, et al. Mol Cancer Res. 2018, doi: 10.1158/1541-7786.MCR-17-0554.