Repurposing crizotinib to target RIPK1-dependent cell death

Authors：Yu, Yajie; Li, Min; Fu, Shufang; He, Xiaoyan; Hu, Xinqian; Zhu, Guofeng; Wang, Jia; You, Xiaoling; Mou, Yan; Ye, Zhi; Wei, Jun^*; Zha, Yunhong^*

Source：International Immunology, 2023, 35(5): 221-230.

DOI：10.1093/intimm/dxac061

• inflammation
• SIRS

Receptor-interacting protein kinase 1 (RIPK1) has emerged as a key regulator of cell death and inflammation, which are implicated in the pathogenesis of many inflammatory and degenerative diseases. RIPK1 is therefore a putative therapeutic target in many of these diseases. However, no pharmacological inhibitor of RIPK1-mediated cell death is currently in clinical use. Recognizing that a repurposed drug has an expedited clinical development pipeline, here we performed a high-throughput drug screen of Food and Drug Administration (FDA)-approved compounds and identified a novel use for crizotinib as an inhibitor of RIPK1-dependent cell death. Furthermore, crizotinib rescued TNF-alpha-induced death in mice with systemic inflammatory response syndrome. RIPK1 kinase activity was directly inhibited by crizotinib. These findings identify a new use for an established compound and are expected to accelerate drug development for RIPK1-spectrum disorders.

• Institution
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