JAK inhibition as a therapeutic strategy for immune and inflammatory diseases

• Published in: Nature reviews. Drug discovery Vol. 16; no. 12; pp. 843 - 862
• Main Authors: Schwartz, Daniella M., Kanno, Yuka, Villarino, Alejandro, Ward, Michael, Gadina, Massimo, O'Shea, John J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2017; Nature Publishing Group
• Subjects: 631/250/127; 631/250/249/1313/498; 631/250/249/2510; 631/250/249/2510/257; 631/250/249/2510/257/1402; 631/92/613; 692/308/153; Animals; Biomedicine; Biotechnology; Cancer Research; Care and treatment; Cellular signal transduction; Clinical trials; Cytokines; Cytokines - immunology; Development and progression; Drug Design; Genetic aspects; Health aspects; Humans; Immune System Diseases - drug therapy; Immune System Diseases - physiopathology; Immunologic diseases; Inflammation - drug therapy; Inflammation - physiopathology; Inflammatory diseases; Janus Kinase Inhibitors - adverse effects; Janus Kinase Inhibitors - pharmacology; Janus Kinase Inhibitors - therapeutic use; Janus Kinases - drug effects; Janus Kinases - metabolism; Medicinal Chemistry; Molecular Medicine; Pharmacology/Toxicology; Phosphotransferases; review-article; Signal Transduction - drug effects
• ISSN: 1474-1776; 1474-1784
• DOI: 10.1038/nrd.2017.201

Key Points
Despite their success, conventional and biologic disease-modifying antirheumatic drugs are not effective in all patients.
First-generation Janus kinase (JAK) inhibitors, or jakinibs, are effective for rheumatoid arthritis and in a number of other autoimmune conditions.
Next-generation selective jakinibs are being developed and are effective in rheumatoid arthritis, inflammatory bowel disease and other autoimmune conditions.
First-generation and second-generation jakinibs are currently being investigated for a number of new indications.
Many of the adverse effects of jakinibs can be linked to the action of the cytokines that are blocked.
Topical jakinibs represent an exciting new class of agents that may preserve therapeutic efficacy while eliminating adverse effects that result from systemic JAK inhibition.
Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines. Jakinibs — small-molecule inhibitors of JAKs — have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies. This Review discusses the biology, development and efficacy of jakinibs in the treatment of immune and inflammatory diseases.
The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens and how best to identify patients who will benefit from jakinibs. This Review discusses the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents and the use of jakinibs in a spectrum of immune and inflammatory diseases.