Design and Synthesis of Novel MEK Inhibitors for the Treatment of Solid Tumors

Aberrant activation of the Ras/Raf/MEK/ERK pathway occurs in more than 30% of human cancers. As part of this pathway, MEK1/2 has crucial roles in tumorigenesis, cell proliferation, and inhibition of Apoptosis. At present, a number of MEK1/2 inhibitors are approved for the treatment of melanoma. However, MEK1/2 inhibitors have poor single-drug efficacy in the treatment of solid tumors and are prone to drug resistance. A series of compounds containing a diarylamine skeleton and phenylacrylamide (acrylamide) have been designed and synthesized in this paper. The most promising compound M15 showed good inhibitory activity of MEK1 (IC₅₀ = 10.29 nM) and good inhibitory effect on three types of solid tumor cells: MDA-MB-231(IC₅₀ = 2.76 μM), HepG2 (IC₅₀ = 2.57 μM) and A549 (IC₅₀ = 5.40 μM). At the same time, M15 was less toxic to human normal cells (MCF-10A IC₅₀ > 20 μM) and has certain stability of liver microsomes in vitro (human, t_1/2 = 27.9 min; rat, t_1/2 > 60 min). It can induce Apoptosis of MDA-MB-231 cells and slow down their migration. Therefore, compound M15 acts as a novel MEK1/2 inhibitor and may be a promising candidate for solid tumor intervention.

MEK1/2; antitumor; inhibitors.