Right open reading frame kinase 2 (RIOK2) is an atypical serine threonine kinase which plays an important role in regulating ribosome synthesis and cell cycle progression. RIOK2 has been implicated in multiple human cancers and is a potential target for cancer treatment. We previously reported the discovery of CQ211 as a potent and selective RIOK2 inhibitor. Herein we present the design, synthesis, and evaluation of the first RIOK2 molecular glue degrader CQ627 based on the structure of CQ211. CQ627 can effectively induce the degradation of RIOK2 with a DC₅₀ value of 410 nM in MOLT4 leukemia cell line via UPS by recruiting E3 ubiquitin ligase RNF126, while the corresponding small molecular inhibitor CQ211 barely induces any degradation at higher concentration of 10 μM. Moreover, CQ627 dose-dependently induces apoptosis and blocks cell cycles in G2/M phase in MOLT4 leukemia cells. Importantly, it also displays stronger antiproliferative activities in a variety of cancer cell lines than RIOK2 inhibitor CQ211 and demonstrates promising in vivo efficacy in a mouse MOLT4 xenograft model.

中文翻译：

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右开阅读框激酶 2 （RIOK2） 分子胶降解剂的第一个例子的发现


右开阅读框激酶 2 （RIOK2） 是一种非典型的丝氨酸苏氨酸激酶，在调节核糖体合成和细胞周期进程中起重要作用。RIOK2 与多种人类癌症有关，是癌症治疗的潜在靶点。我们之前报道了 CQ211 作为一种有效的选择性 RIOK2 抑制剂的发现。本文介绍了基于 CQ211 结构的首个 RIOK2 分子胶降解剂 CQ627 的设计、合成和评价。CQ627 可通过募集 E3 泛素连接酶 RNF126 通过 UPS 有效诱导 MOLT4 白血病细胞系中 RIOK2 的降解，DC₅₀ 值为 410 nM，而相应的小分子抑制剂 CQ211 在 10 μM 的较高浓度下几乎不诱导任何降解。此外，CQ627 剂量依赖性地诱导 MOLT4 白血病细胞凋亡并阻断 G2/M 期的细胞周期。重要的是，它还在多种癌细胞系中显示出比 RIOK2 抑制剂 CQ211 更强的抗增殖活性，并在小鼠 MOLT4 异种移植模型中显示出有希望的体内疗效。