Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader

MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) are the
“gatekeepers”
of the ERK signaling output with redundant roles in controlling ERK
activity. Numerous inhibitors targeting MEK1/2 have been developed
including three FDA-approved drugs. However, acquired resistance to
MEK1/2 inhibitors has been observed in patients, and new therapeutic
strategies are needed to overcome the resistance. Here, we report
a first-in-class degrader of MEK1/2, MS432 (23), which
potently and selectively degraded MEK1 and MEK2 in a VHL E3 ligase-
and proteasome-dependent manner and suppressed ERK phosphorylation
in cells. It inhibited colorectal cancer and melanoma cell proliferation
much more effectively than its negative control MS432N (24), and its effect was phenocopied by MEK1/2 knockdown. Compound 23 was highly selective for MEK1/2 in global proteomic profiling
studies. It was also bioavailable in mice and can be used for in vivo
efficacy studies. We provide two well-characterized chemical tools
to the biomedical community.