Therapeutic targeting of Janus kinases.
Cytokines play pivotal roles in immunity and inflammation, and targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors associate with Janus family kinases (JAKs) to effect intracellular signaling. These structurally unique protein kinases play essential and specific roles in immune cell development and function. One JAK, JAK3, has particularly selective functions. Mutations of this kinase underlie severe combined immunodeficiency, indicative of its critical role in the development and function of lymphocytes. Because JAK3 appears not to have functions outside of hematopoietic cells, this kinase has been viewed as an excellent therapeutic target for the development of a new class of immunosuppressive drugs. In fact, several companies are developing JAK3 inhibitors, and Phase II studies are underway. Mutations of Tyk2 cause autosomal recessive hyperIgE syndrome, and in principle, Tyk2 inhibitors might also be useful as immunosuppressive drugs. JAK2 gain-of-function mutations (V617F) underlie a subset of disorders collectively referred to as myeloproliferative diseases and phase 2 trials using JAK inhibitors are underway in this setting. Thus, we are learning a great deal about the feasibility and effectiveness of targeting Janus kinases, and it appears likely that this will be a fruitful strategy in a variety of settings.
Pesu
Marko
M
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
Laurence
Arian
A
Kishore
Nandini
N
Zwillich
Samuel H
SH
Chan
Gary
G
O'Shea
John J
JJ
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D002986:Clinical Trials as Topic; D006084:Graft Rejection / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D007589:Job Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D018909:src Homology Domains / Q000187:drug effects
D047428:Protein Kinase Inhibitors; D053612:Janus Kinases; D053634:TYK2 Kinase