The Use of a Chemical Biology in the Development of a Novel MEK1/2 Inhibitor

Trametinib is a new anti-cancer drug that was developed by a cell-based phenotypic screening for the accumulation of CDK inhibitor p15INK4b and the growth inhibition in human colorectal cancer cell line HT-29 cells. Therefore, its molecular mechanism remained unknown at the beginning of the development process. To address this issue, we used a chemical biology approach. As a result, we identified MEK1/2 kinase as a molecular target by compound-immobilized affinity chromatography. Trametinib directly binds to MEK1 and MEK2, and allosterically inhibits their kinase activities. It was also shown that trametinib suppresses the phosphorylation status of MEK and ERK in HT-29 cells. We further confirmed that trametinib preferentially inhibits the growth of cancer cell lines harboring BRAF mutation and observed significant antitumor activity in a tumor xenograft model. In 2013, trametinib was approved as a first-in-class MEK inhibitor by the U.S. Food and Drug Administration for the treatment of metastatic melanoma with BRAF V600E or V600K mutations.