7VBT

Crystal structure of RIOK2 in complex with CQ211

Summary for 7VBT

• Entry DOI: 10.2210/pdb7vbt/pdb
• Descriptor: Serine/threonine-protein kinase RIO2, 8-(6-methoxypyridin-3-yl)-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]-5H-[1,2,3]triazolo[4,5-c]quinolin-4-one (3 entities in total)
• Functional Keywords: riok2, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 75148.01

Authors

Zhu, C.,Zhang, Z.M. (deposition date: 2021-09-01, release date: 2022-07-06, Last modification date: 2023-11-29)

Primary citation

Ouyang, Y.,Si, H.,Zhu, C.,Zhong, L.,Ma, H.,Li, Z.,Xiong, H.,Liu, T.,Liu, Z.,Zhang, Z.,Zhang, Z.M.,Cai, Q.
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.
J.Med.Chem., 65:7833-7842, 2022

PubMed 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 , the most potent and selective RIOK2 inhibitor reported so far. displays a high binding affinity ( = 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- 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.

PubMed: 35584513
DOI: 10.1021/acs.jmedchem.2c00271

Experimental method

X-RAY DIFFRACTION (2.54001480108 Å)