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

被引：330

作者：

Mifflin, Lauren ^{[1
]}

Ofengeim, Dimitry ^{[2
]}

Yuan, Junying ^{[1
]}

机构：

[1] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[2] Sanofi, Rare & Neurol Dis Res, Framingham, MA USA

来源：

NATURE REVIEWS DRUG DISCOVERY | 2020年 / 19卷 / 08期

关键词：

NEUTROPHIL EXTRACELLULAR TRAPS; KAPPA-B PATHWAY; CELL-DEATH; NECROSTATIN-1; PROTECTS; INCONTINENTIA PIGMENTI; NECROPTOSIS INHIBITOR; ISCHEMIC-STROKE; A20; DEFICIENCY; HIGHLY POTENT; TNF RECEPTOR;

D O I：

10.1038/s41573-020-0071-y

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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.

引用

页码：553 / 571

页数：19

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