8X2O

RIPK2 in complex with K252

Summary for 8X2O

• Entry DOI: 10.2210/pdb8x2o/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 2, ~{N}-[(1~{R})-4-[4-[(6-fluoranyl-1,3-benzothiazol-5-yl)amino]thieno[2,3-d]pyrimidin-6-yl]cyclohex-3-en-1-yl]cyclopropanecarboxamide (3 entities in total)
• Functional Keywords: inhibitor, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 73558.63

Authors

Yang, J.H.,Yang, J.H. (deposition date: 2023-11-10, release date: 2024-11-13, Last modification date: 2025-08-06)

Primary citation

Chen, Y.,Yuan, X.,Yan, W.,Zou, Y.,Wei, H.,Wei, Y.,Tang, M.,Chen, Y.,Ma, Z.,Yang, T.,Liu, K.,Xiong, B.,Hu, X.,Yang, J.,Chen, L.
CMD-OPT model enables the discovery of a potent and selective RIPK2 inhibitor as preclinical candidate for the treatment of acute liver injury.
Acta Pharm Sin B, 15:3708-3724, 2025

PubMed Abstract: Acute liver injury (ALI) serves as a critical precursor and major etiological factor in the progression and ultimate manifestation of various hepatic disorders. The prevention and treatment of ALI is still a serious global challenge. Given the limited therapeutic options for ALI, exploring novel targeted therapeutic agents becomes imperative. The potential therapeutic efficacy of inhibiting RIPK2 is highlighted, as it may provide significant benefits by attenuating the MAPK pathway and NF-B signaling. Herein, we propose a CMD-OPT model, a two-stage molecular optimization tool for the rapid discovery of RIPK2 inhibitors with optimal properties. Compound , which targets the ATP binding site, demonstrated excellent kinase specificity, ideal oral pharmacokinetics, and superior therapeutic effects in a model of APAP-induced ALI, positioning as a promising preclinical candidate. This marks the first application of RIPK2 inhibitors in ALI treatment, opening a novel therapeutic pathway for clinical applications. These results highlight the efficacy of the CMD-OPT model in producing lead compounds from known active molecules, showcasing its significant potential in drug discovery.

PubMed: 40698146
DOI: 10.1016/j.apsb.2025.05.003

Experimental method

X-RAY DIFFRACTION (2.26 Å)