Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Proliferation
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Humans
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MAP Kinase Kinase 1 / antagonists & inhibitors*
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MAP Kinase Kinase 1 / metabolism
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MAP Kinase Kinase 2 / antagonists & inhibitors*
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MAP Kinase Kinase 2 / metabolism
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Mice
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphatidylinositol 3-Kinases / chemistry
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Proteolysis
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / metabolism
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology*
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Signal Transduction
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Small Molecule Libraries / pharmacology*
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Structure-Activity Relationship
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Thiazoles / chemistry
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Thiazoles / pharmacokinetics
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Thiazoles / pharmacology*
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Tissue Distribution
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Tumor Cells, Cultured
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CRBN protein, human
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Protein Kinase Inhibitors
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Pyrrolidines
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Small Molecule Libraries
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Thiazoles
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Ubiquitin
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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MAP2K2 protein, human
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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VHL protein, human