Proteolysis targeting chimera (PROTAC) technology has emerged over the last two decades as a powerful tool for targeted degradation of endogenous proteins. Herein we describe the development of PROTACs for receptor tyrosine kinases, a protein family yet to be targeted for induced protein degradation. The use of VHL-recruiting PROTACs against this protein family reveals several advantages of degradation over inhibition alone: direct comparisons of fully functional, target-degrading PROTACs with target-inhibiting variants that contain an inactivated E3 ligase-recruiting ligand show that degradation leads to more potent inhibition of cell proliferation and a more durable and sustained downstream signaling response, and thus addresses the kinome rewiring challenge seen with many receptor tyrosine kinase inhibitors. Combined, these findings demonstrate the ability to target receptor tyrosine kinases for degradation using the PROTAC technology and outline the advantages of this degradation-based approach.

中文翻译：

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靶向蛋白质降解优于抑制的优势：RTK 案例研究

蛋白水解靶向嵌合体 (PROTAC) 技术在过去二十年中出现，成为靶向降解内源性蛋白质的强大工具。在此，我们描述了受体酪氨酸激酶 PROTAC 的开发，受体酪氨酸激酶是一个尚未被靶向诱导蛋白质降解的蛋白质家族。使用 VHL 募集 PROTAC 对抗该蛋白质家族揭示了降解相对于单独抑制的几个优势：直接比较功能齐全的靶向降解 PROTAC 与含有失活 E3 连接酶募集配体的靶向抑制变体表明降解导致更多有效抑制细胞增殖和更持久和持续的下游信号反应，从而解决许多受体酪氨酸激酶抑制剂所见的激酶组重新布线挑战。结合起来，