Selectivity and therapeutic inhibition of kinases: to be or not to be?
Protein kinases, which serve critical functions in signaling pathways in all cells, are popular therapeutic targets. At present, eight kinase inhibitors have been approved in the United States, each of which shows nanomolar potency. Although the initial goal was to generate inhibitors with a high degree of selectivity, recent experience has revealed that many of these approved compounds target more than one kinase. Surprisingly, this promiscuity is less problematic than one would have imagined; indeed, it opens new therapeutic opportunities. In this Perspective, we discuss the present status of Janus kinase inhibitors-a new class of immunosuppressive drugs-and the advantages and disadvantages of selectively inhibiting this class of kinase.
Ghoreschi
Kamran
K
Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA. ghoreschik@mail.nih.gov
Laurence
Arian
A
O'Shea
John J
JJ
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology; D010766:Phosphorylation; D011087:Polycythemia Vera / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D053612:Janus Kinases