Kinase inhibitors: a new approach to rheumatoid arthritis treatment.
OBJECTIVE
Due to the cost and parenteral mode of administration of biologics, efforts to develop oral small molecule inhibitors to protein kinases involved in cellular signaling that impact inflammatory cytokine production have been ongoing. This article will review the recent publications on these efforts.


RESULTS
On preclinical work, p38 mitogen-activated kinases were considered attractive targets to suppress cytokine production. Three different molecules (SCIO_469, Pamapimod, VX-702) that target the p38alpha isoform have been evaluated in phase 2 trials. Unfortunately, clinical efficacy was not observed, and dose-related toxicity was seen. The future of this approach is unclear. Targeting more upstream protein tyrosine kinases such as spleen tyrosine kinase (SyK) and the JAK family of kinases has been associated with greater success in clinical trials, with efficacy demonstrated. Adverse events occurred in a dose-dependent fashion with the SyK inhibitor, such as diarrhea and hypertension. Neutropenia, elevated liver-function tests, serum creatinine elevations and lipid elevations have occurred with JAK-kinase inhibition. Dose modifications have been made based on the phase 2 trial results; phase 3 clinical trials are ongoing.


CONCLUSIONS
Inhibiting downstream proteins involved in cellular signaling, such as p38, has not been successful to date. Inhibitors of more upstream protein-tyrosine kinases involved in cellular signaling appear to be viable molecular candidates for rheumatoid arthritis. If the results seen in phase 2 studies are confirmed in larger phase 3 studies, we may soon have new, oral DMARD therapies available.
Cohen
Stanley
S
Metroplex Clinical Research Center, Dallas, Texas, USA. arthdoc@aol.com
Fleischmann
Roy
R
D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D053612:Janus Kinases / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D012219:Rheumatology / Q000379:methods / Q000639:trends; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016207:Cytokines; D047428:Protein Kinase Inhibitors; D053612:Janus Kinases