Journal Article

Targeting RIPK1 for the treatment of human diseases

Yuan, Junying, Ofengeim, Dimitry, Degterev, Alexei

2019

Overview

RIPK1 kinase has emerged as a promising therapeutic target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases. This was supported by extensive studies which demonstrated that RIPK1 is a key mediator of apoptotic and necrotic cell death as well as inflammatory pathways. Furthermore, human genetic evidence has linked the dysregulation of RIPK1 to the pathogenesis of ALS as well as other inflammatory and neurodegenerative diseases. Importantly, unique allosteric small-molecule inhibitors of RIPK1 that offer high selectivity have been developed. These molecules can penetrate the blood–brain barrier, thus offering the possibility to target neuroinflammation and cell death which drive various neurologic conditions including Alzheimer’s disease, ALS, and multiple sclerosis as well as acute neurological diseases such as stroke and traumatic brain injuries. We discuss the current understanding of RIPK1 regulatory mechanisms and emerging evidence for the pathological roles of RIPK1 in human diseases, especially in the context of the central nervous systems.

• Publisher: National Academy of Sciences
• Subject: Allosteric properties / Amyotrophic lateral sclerosis / Apoptosis / Biological Sciences / Blood-brain barrier / Cell Biology / Cell death / Central Nervous System Diseases - drug therapy / Drug Development / Gene Expression / Head injuries / Humans / INAUGURAL ARTICLE / Inflammation - metabolism / Inflammatory diseases / Kinases / Molecular Targeted Therapy / Multiple sclerosis / Necroptosis / Neurodegenerative diseases / Neurological diseases / Pathogenesis / Receptor-Interacting Protein Serine-Threonine Kinases - antagonists & inhibitors / Regulatory mechanisms (biology) / Selectivity / Therapeutic applications / Traumatic brain injury / Tumor Necrosis Factor-alpha - metabolism