Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, USA.
Arvinas, LLC, 5 Science Park, New Haven, CT, USA.
Cell Chem Biol. 2018 Jan 18;25(1):67-77.e3. doi: 10.1016/j.chembiol.2017.09.009. Epub 2017 Nov 9.
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.
在过去的二十年中，蛋白酶体靶向嵌合体（PROTAC）技术已经成为一种强大的工具，可用于靶向降解内源性蛋白质。在此，我们描述了针对受体酪氨酸激酶的 PROTAC 的开发，这是一个尚未针对诱导蛋白降解进行靶向的蛋白质家族。使用 VHL 招募的 PROTAC 针对该蛋白家族进行研究，揭示了降解相对于单独抑制的几个优势：完全功能的、靶向降解的 PROTAC 与含有失活 E3 连接酶招募配体的靶向抑制变体的直接比较表明，降解导致更有效的细胞增殖抑制和更持久和持续的下游信号转导反应，从而解决了许多受体酪氨酸激酶抑制剂所面临的激酶组重排挑战。综上所述，这些发现证明了使用 PROTAC 技术靶向受体酪氨酸激酶进行降解的能力，并概述了这种基于降解的方法的优势。
