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Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-07 , DOI: 10.1021/acs.jmedchem.0c01609
Jianping Hu 1 , Jieli Wei 1 , Hyerin Yim 1 , Li Wang 2 , Ling Xie 2 , Margaret S Jin 1 , Md Kabir 1 , Lihuai Qin 1 , Xian Chen 2 , Jing Liu 1 , Jian Jin 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-07 , DOI: 10.1021/acs.jmedchem.0c01609
Jianping Hu 1 , Jieli Wei 1 , Hyerin Yim 1 , Li Wang 2 , Ling Xie 2 , Margaret S Jin 1 , Md Kabir 1 , Lihuai Qin 1 , Xian Chen 2 , Jing Liu 1 , Jian Jin 1
Affiliation
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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.
中文翻译：
有效且选择性的丝裂原激活蛋白激酶激酶 1/2 (MEK1/2) 异双功能小分子降解剂
此前，我们报道了一种一流的 von Hippel–Lindau (VHL) 招募丝裂原激活蛋白激酶激酶 1 和 2 (MEK1/2) 降解剂 MS432。迄今为止，仅发表了两篇 MEK1/2 降解剂论文，并且报道的构效关系 (SAR) 非常有限。在这里，我们描述了我们广泛的 SAR 研究，探索了 von Hippel-Lindau (VHL) 和 cereblon (CRBN) E3 连接酶配体和各种接头，从而产生了两种新型、改进的 VHL 招募 MEK1/2 降解剂， 24 (MS928)和27 (MS934)，以及第一个CRBN招募MEK1/2降解器50 (MS910)。这些化合物通过劫持泛素蛋白酶体系统，有效地、选择性地降解 MEK1/2，抑制下游信号传导，并抑制癌细胞增殖。此外，同时抑制BRAF或PI3K显着增强了降解剂27的抗肿瘤活性，表明MEK1/2降解与BRAF或PI3K抑制的组合可能提供潜在的治疗益处。最后，除了更有效之外，降解剂27还显示出小鼠体内血浆暴露水平的改善，代表了迄今为止体内研究中最好的 MEK1/2 降解剂。
更新日期：2020-12-24
中文翻译：
有效且选择性的丝裂原激活蛋白激酶激酶 1/2 (MEK1/2) 异双功能小分子降解剂
此前，我们报道了一种一流的 von Hippel–Lindau (VHL) 招募丝裂原激活蛋白激酶激酶 1 和 2 (MEK1/2) 降解剂 MS432。迄今为止，仅发表了两篇 MEK1/2 降解剂论文，并且报道的构效关系 (SAR) 非常有限。在这里，我们描述了我们广泛的 SAR 研究，探索了 von Hippel-Lindau (VHL) 和 cereblon (CRBN) E3 连接酶配体和各种接头，从而产生了两种新型、改进的 VHL 招募 MEK1/2 降解剂， 24 (MS928)和27 (MS934)，以及第一个CRBN招募MEK1/2降解器50 (MS910)。这些化合物通过劫持泛素蛋白酶体系统，有效地、选择性地降解 MEK1/2，抑制下游信号传导，并抑制癌细胞增殖。此外，同时抑制BRAF或PI3K显着增强了降解剂27的抗肿瘤活性，表明MEK1/2降解与BRAF或PI3K抑制的组合可能提供潜在的治疗益处。最后，除了更有效之外，降解剂27还显示出小鼠体内血浆暴露水平的改善，代表了迄今为止体内研究中最好的 MEK1/2 降解剂。
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