Discovery of 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ211) as a Highly Potent and Selective RIOK2 Inhibitor

Abstract

RIOK2 is an atypical kinase implicated in multiple human cancers. Although recent studies establish the role of RIOK2 in ribosome maturation and cell cycle progression, its biological functions remain poorly elucidated, hindering the potential to explore RIOK2 as a therapeutic target. Here, we report the discovery of CQ211, the most potent and selective RIOK2 inhibitor reported so far. CQ211 displays a high binding affinity (K d = 6.1 nM) and shows excellent selectivity to RIOK2 in both enzymatic and cellular studies. It also exhibits potent proliferation inhibition activity against multiple cancer cell lines and demonstrates promising in vivo efficacy in mouse xenograft models. The crystal structure of RIOK2-CQ211 sheds light on the molecular mechanism of inhibition and informs the subsequent optimization. The study provides a cell-active chemical probe for verifying RIOK2 functions, which may also serve as a leading molecule in the development of therapeutic RIOK2 inhibitors.

Each Interruption is an Opportunity: Novel Synthetic Strategies Explored Through Interrupted Click Reactions

“…Molecular docking studies revealed interactions within the ATP binding site on RIO kinase, allowing for a targeted optimization process that led to the preparation of compound CQ211, characterized by high potency (K d = 6.1 nM) and excellent selectivity profile against this atypical kinase (Figure 3). [48] Triazoloquinazolinones 71 have been obtained through a reaction between terminal alkynes 14 and 2-azido-N-methoxybenzamides 70 (Scheme 25 and 26). [49] In this case as well, the best catalyst remains CuI, along with DIPEA, in THF in the presence of air.…”

A transition-metal-free azide–alkyne cycloaddition/hydroamination cascade reaction for the construction of triazole-fused piperazin-2-ones

“…Thus, development of efficient methods for the construction of 1,2,3-triazole fused heterocycles with substitution diversity is highly appealing. As part of our efforts to develop novel tandem reactions for the construction of fused 1,2,3-triazole compounds, 12 herein we would like to report a transition-metal-free [3 + 2] cycloaddition/intramolecular hydroamination tandem reaction of sodium azide with N -(prop-2-yn-1-yl)propiolamides for the formation of [1,2,3]triazolo [1,5- a ]pyrazin-4(5 H )-ones (Scheme 1c).…”

Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors

“…Very recently, we have identified a class of [1,2,3] triazolo [4,5-c]quinolin-4-one compounds as novel RIOK2 inhibitors. 20,21 The representative compound 7 (CQ211, Fig. 1) displayed high binding affinity (K d = 6.1 nM) and showed excellent selectivity to RIOK2 in both enzymic and cellular studies.…”