TY - JOUR AU - Wang Zuo-wei AU - Zou Feng-ming AU - Wang Ao-li AU - Yang Jing AU - Jin Rui AU - Wang Bei-lei AU - Shen Li-juan AU - Qi Shuang AU - Liu Juan AU - Liu Jing AU - Wang Wen-chao AU - Liu Qing-song PY - 2023 TI - Repurposing of the FGFR inhibitor AZD4547 as a potent inhibitor of necroptosis by selectively targeting RIPK1 JF - Acta Pharmacologica Sinica; Vol 44, No 4 (April 2023): Acta Pharmacologica Sinica Y2 - 2023 KW - N2 - Necroptosis is a form of regulated necrosis involved in various pathological diseases. The process of necroptosis is controlled by receptor-interacting kinase 1 (RIPK1), RIPK3, and pseudokinase mixed lineage kinase domain-like protein (MLKL), and pharmacological inhibition of these kinases has been shown to have therapeutic potentials in a variety of diseases. In this study, using drug repurposing strategy combined with high-throughput screening (HTS), we discovered that AZD4547, a previously reported FGFR inhibitor, is able to interfere with necroptosis through direct targeting of RIPK1 kinase. In both human and mouse cell models, AZD4547 blocked RIPK1-dependent necroptosis. In addition, AZD4547 rescued animals from TNF-induced lethal shock and inflammatory responses. Together, our study demonstrates that AZD4547 is a potent and selective inhibitor of RIPK1 with therapeutic potential for the treatment of inflammatory disorders that involve necroptosis. UR - http://www.chinaphar.com/article/view/10805