Discovery of the First Examples of Right Open Reading Frame Kinase 2 (RIOK2) Molecular Glue Degraders

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. [Display omitted] •Discovery of the first classes of RIOK2 molecular glue degraders.•CQ627 induced the degradation of RIOK2 via UPS with a DC50 of 410 nM in MOLT4 cell.•CQ627 demonstrated promising in vitro and in vivo antitumor efficacy.