Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders

Previously, we reported a first-in-class
von Hippel–Lindau
(VHL)-recruiting mitogen-activated protein kinase kinases 1 and 2
(MEK1/2) degrader, MS432. To date, only two MEK1/2 degrader papers
have been published and very limited structure–activity relationships
(SAR) have been reported. Here, we describe our extensive SAR studies
exploring both von Hippel–Lindau (VHL) and cereblon (CRBN)
E3 ligase ligands and a variety of linkers, which resulted in two
novel, improved VHL-recruiting MEK1/2 degraders, 24 (MS928)
and 27 (MS934), and the first CRBN-recruiting MEK1/2
degrader 50 (MS910). These compounds potently and selectively
degraded MEK1/2 by hijacking the ubiquitin-proteasome system, inhibited
downstream signaling, and suppressed cancer cell proliferation. Furthermore,
concurrent inhibition of BRAF or PI3K significantly potentiated the
antitumor activity of degrader 27, suggesting that the
combination of MEK1/2 degradation with BRAF or PI3K inhibition may
provide potential therapeutic benefits. Finally, besides being more
potent, degrader 27 displayed improved plasma exposure
levels in mice, representing the best MEK1/2 degrader to date for
in vivo studies.