Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York , New York 10029 , United States.
J Med Chem. 2020 Feb 13;63(3):1216-1232. doi: 10.1021/acs.jmedchem.9b01566. Epub 2020 Jan 14.
Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed and approved by Food and Drug Administration for the treatment of non-small-cell lung cancers, but their efficacy can be compromised by acquired drug resistance conferred by -mutant variants. Here, we described the discovery of a novel E3 ligase von Hippel-Lindau-recruiting EGFR degrader, MS39 (compound ), and a first-in-class E3 ligase cereblon-recruiting EGFR degrader, MS154 (compound ), using the proteolysis targeting chimera technology. These compounds potently induced the degradation of mutant but not wild-type EGFR in an E3 ligase-dependent manner in cancer cell lines and effectively suppressed the growth of lung cancer cells compared with the corresponding negative controls. The global proteomic analyses revealed that the compounds were highly selective for EGFR. Furthermore, both compounds were bioavailable in mouse pharmacokinetic studies, and compound is the first EGFR degrader suitable for in vivo efficacy studies. Overall, we provide a set of well-characterized chemical tools to the research community.
几种表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂已被食品和药物管理局开发和批准用于治疗非小细胞肺癌，但它们的疗效可能会受到突变变体赋予的获得性耐药性的影响。在这里，我们描述了使用蛋白水解靶向嵌合体技术发现新型 E3 连接酶 von Hippel-Lindau 募集 EGFR 降解剂 MS39（化合物 ）和新型 E3 连接酶 cereblon 募集 EGFR 降解剂 MS154（化合物 ）。这些化合物在癌症细胞系中以 E3 连接酶依赖性方式强烈诱导突变型但不诱导野生型 EGFR 的降解，并与相应的阴性对照相比有效地抑制了肺癌细胞的生长。全面蛋白质组学分析表明，这些化合物对 EGFR 具有高度选择性。此外，在小鼠药代动力学研究中，这两种化合物均具有生物利用度，并且化合物 是第一个适合体内疗效研究的 EGFR 降解剂。总体而言，我们为研究界提供了一组经过良好表征的化学工具。
