RO5068760

RO5068760 is a potent, orally active and selective non-ATP-competitive MEK1/2 inhibitor with an IC₅₀ of 0.025 μM for MEK1. RO5068760 significantly inhibits MAPK pathway activity, thereby inducing G1 cell cycle arrest and apoptosis to inhibit cancer cell growth. RO5068760 exhibits significant efficacy in a broad spectrum of tumors with aberrant MAPK pathway activation. RO5068760 can be used for melanoma, colorectal cancer, non-small cell lung cancer (NSCLC), and pancreatic cancer research^[1]. In Vitro:RO5068760 significantly inhibits MAPK pathway activity as evidenced by the dose-dependent inhibition of both ERK and MEK phosphorylation (p-ERK and p-MEK) in many human cancer cell lines, such as LOX, HT-29, H460, and MIA PaCa-2 cells^[1].
RO5068760 specifically inhibits cell growth in cancer cell lines with activating pathway gene mutations (B-Raf or KRas), and the representative IC₅₀/IC₉₀ values are 0.018/0.72 μM in LOX (B-RafV600E), 0.11/0.56 μM in HT-29 (B-RafV600E), 0.30/3.08 μM in H460 (KRasG12C), and 1.25/5.11 μM in MIA PaCa-2 (KRasQ61K) cancer cells^[1].
RO5068760 (0-10 μM, 24 h) downregulates CDK4/cyclin D1 and upregulates p27 and cleaved PARP in responsive cancer cells (HT-29 and LOX), indicating that it induces G1 cell cycle arrest and subsequently leads to apoptosis^[1]. In Vivo:RO5068760 (6.25-500 mg/kg, p.o., b.i.d. or q.d. or weekly for approximately 3 to 4 weeks) exhibits dose-dependent antitumor activity in corresponding human tumor xenograft models in mice with aberrant MAPK pathway activation^[1].