| Literature DB >> 33284613 |
Jianping Hu1, Jieli Wei1, Hyerin Yim1, Li Wang2, Ling Xie2, Margaret S Jin1, Md Kabir1, Lihuai Qin1, Xian Chen2, Jing Liu1, Jian Jin1.
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.Entities:
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Year: 2020 PMID： 33284613 PMCID： PMC7770057 DOI： 10.1021/acs.jmedchem.0c01609
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446