LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Department of Cancer Biology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
Leukemia. 2019 Nov;33(11):2685-2694. doi: 10.1038/s41375-019-0467-z. Epub 2019 Apr 8.
Proteasome inhibition is an effective treatment for multiple myeloma (MM); however, targeting different components of the ubiquitin-proteasome system (UPS) remains elusive. Our RNA-interference studies identified proteasome-associated ubiquitin-receptor Rpn13 as a mediator of MM cell growth and survival. Here, we developed the first degrader of Rpn13, WL40, using a small-molecule-induced targeted protein degradation strategy to selectively degrade this component of the UPS. WL40 was synthesized by linking the Rpn13 covalent inhibitor RA190 with the cereblon (CRBN) binding ligand thalidomide. We show that WL40 binds to both Rpn13 and CRBN and triggers degradation of cellular Rpn13, and is therefore first-in-class in exploiting a covalent inhibitor for the development of degraders. Biochemical and cellular studies show that WL40-induced Rpn13 degradation is both CRBN E3 ligase- and Rpn13-dependent. Importantly, WL40 decreases viability in MM cell lines and patient MM cells, even those resistant to bortezomib. Mechanistically, WL40 interrupts Rpn13 function and activates caspase apoptotic cascade, ER stress response and p53/p21 signaling. In animal model studies, WL40 inhibits xenografted human MM cell growth and prolongs survival. Overall, our data show the development of the first UbR Rpn13 degrader with potent anti-MM activity, and provide proof of principle for the development of degraders targeting components of the UPS for therapeutic application.
蛋白酶体抑制是多发性骨髓瘤（MM）的有效治疗方法；然而，靶向泛素蛋白酶体系统（UPS）的不同成分仍然难以实现。我们的 RNA 干扰研究确定蛋白酶体相关泛素受体 Rpn13 是 MM 细胞生长和存活的介质。在这里，我们使用小分子诱导的靶向蛋白降解策略开发了第一个 Rpn13 降解剂 WL40，以选择性降解 UPS 的这一组成部分。WL40 通过将 Rpn13 共价抑制剂 RA190 与 cereblon (CRBN) 结合配体沙利度胺连接而合成。我们表明，WL40 与 Rpn13 和 CRBN 结合并触发细胞 Rpn13 的降解，因此是第一个利用共价抑制剂开发降解剂的药物。生化和细胞研究表明，WL40 诱导的 Rpn13 降解既依赖于 CRBN E3 连接酶，也依赖于 Rpn13。重要的是，WL40 降低了 MM 细胞系和患者 MM 细胞的活力，即使是对硼替佐米耐药的细胞。从机制上讲，WL40 中断了 Rpn13 的功能并激活了 caspase 凋亡级联、内质网应激反应和 p53/p21 信号通路。在动物模型研究中，WL40 抑制异种移植的人 MM 细胞生长并延长存活时间。总的来说，我们的数据表明开发了第一个具有强大抗 MM 活性的 UbR Rpn13 降解剂，并为开发针对 UPS 成分的降解剂用于治疗应用提供了原理证明。
