SCH-772984

A novel potent and selective inhibitor of ERK1/ERK2 with IC50 of 4 nM/1 nM, respectively; is highly selective, with only seven kinases of 300 showing >50% inhibition at 1 uM; prevents MEK-mediated ERK phosphorylation, reduces pCRAF S289/S296/S301 phosphorylation; has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models.Colon Cancer Phase 1 Clinical (In Vitro) :SCH772984 (300 nM; 24-48hours) results in a G1 arrest in SCH772984-sensitive melanoma cells.SCH772984 (3-300 nM; 24 hours) inhibits ERK and RSK phosphorylation.SCH772984 shows EC50 values less than 500 nM in approximately 88% and 49% of BRAF-mutant (n=25) or RAS-mutant (n=35) tumor lines, respectively. (In Vivo) :SCH772984 (12.5-50 mg/kg; i.p.; twice daily for 14 days) leads to 98% tumor regression.Dose-dependent antitumor activity is also observed in the KRAS-mutant pancreatic MiaPaCa model, with 36% regression at 50 mg/kg twice daily. Importantly, tumor regression is accompanied by robust inhibition of ERK phosphorylation in tumor tissue. SCH772984 is well tolerated on this schedule as measured by morbidity, lethality, or body weight loss.