受体相互作用蛋白激酶 1（RIPK1）作为治疗靶点。

Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

Rare and Neurologic Disease Research, Sanofi, Framingham, MA, USA.

Nat Rev Drug Discov. 2020 Aug;19(8):553-571. doi: 10.1038/s41573-020-0071-y. Epub 2020 Jul 15.

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.

受体相互作用丝氨酸/苏氨酸蛋白激酶 1（RIPK1）是细胞死亡和炎症的关键介质。RIPK1 变构调节域中的独特疏水性口袋使开发其激酶活性的高选择性小分子抑制剂成为可能，这些抑制剂在临床前模型和临床试验中表现出安全性。这些 RIPK1 抑制剂在治疗单基因和多基因自身免疫、炎症、神经退行性、缺血和急性疾病（如败血症）方面的潜在应用正在出现。本文综述了 RIPK1 生物学和 RIPK1 信号通路中的疾病相关突变，重点介绍了 RIPK1 抑制剂的临床试验和减轻开发挑战的潜在策略。