Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells.

The RAF/MEK/ERK pathway is a crucial signal path which is closely associated with the proliferation, differentiation, and apoptosis of tumors. MEK1/2 is a key kinase target in the pathway, with ERK1/2 acting as the main substrate of it. Despite the rapid development of MEK1/2 inhibitors, acquired resistance still happens and remains a significant problem. Most of the inhibitors possess a similar diarylamine scaffold. Here we designed and synthesized a series of MEK1/2 degraders based on a coumarin derivative which was a potent non-diarylamine allosteric MEK1/2 inhibitor. P6b among them showed the most potent degradation effect, with DC 50 values of 0.3 μM and 0.2 μM in MEK1 and MEK2 degradation, respectively. An antiproliferation assay showed that it more significantly inhibits the growth of A375 cells (IC 50 = 2.8 μM) compared to A549 cells (IC 50 = 27.3 μM). To sum up, we discovered P6b with a non-diarylamine scaffold for the first time as a potent MEK PROTAC effective in human cancer cells.