Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors

Right open reading frame kinase 2 (RIOK2) is an atypical kinase and has been proved to be involved in multiple human cancers including non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), glioblastoma and anemia. Although tremendous efforts have been devoted to the studies of RIOK2, its biological functions remain poorly understood. It is highly important to develop potent and selective RIOK2 inhibitors as potential research tools to elucidate its functions and as drug candidates for further therapies. We have previously identified a highly potent and selective RIOK2 inhibitor (CQ211). To confirm the importance of the "V-shaped" structure of CQ211 for binding with RIOK2, a variety of tricyclic compounds with different core structures instead of the [1,2,3]triazolo[4,5-c]quinolin-4-one core of CQ211 were designed, synthesized, and the binding affinities of these tricyclic heterocycles with RIOK2 were also evaluated.