Receptor-interacting protein kinase 1 (RIPK1) as a therapeutic target

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a key mediator of cell death and inflammation. The unique hydrophobic pocket in the allosteric regulatory domain of RIPK1 has enabled the development of highly selective small-molecule inhibitors of its kinase activity, which have demonstrated safety in preclinical models and clinical trials. Potential applications of these RIPK1 inhibitors for the treatment of monogenic and polygenic autoimmune, inflammatory, neurodegenerative, ischaemic and acute conditions, such as sepsis, are emerging. This article reviews RIPK1 biology and disease-associated mutations in RIPK1 signalling pathways, highlighting clinical trials of RIPK1 inhibitors and potential strategies to mitigate development challenges. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) - a key mediator of cell death and inflammation - is activated in human diseases. Here, Yuan and colleagues discuss current understanding of RIPK1 biology and its association with diseases including inflammatory and autoimmune disorders, neurodegenerative diseases and sepsis. The clinical development of small-molecule RIPK1 inhibitors and associated challenges are discussed.