Published online Sep 18, 2014. doi: 10.5312/wjo.v5.i4.496
Revised: June 5, 2014
Accepted: June 20, 2014
Published online: September 18, 2014
Medicinal chemistry strategies have contributed to the development, experimental study of and clinical trials assessment of the first type of protein kinase small molecule inhibitor to target the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway. The orally administered small molecule inhibitor, tofacitinib, is the first drug to target the JAK/STAT pathway for entry into the armamentarium of the medical therapy of rheumatoid arthritis. The introduction of tofacitinib into general rheumatologic practice coupled with increasing understanding that additional cellular signal transduction pathways including the mitogen-activated protein kinase and phosphatidylinositide-3-kinase/Akt/mammalian target of rapamycin pathways as well as spleen tyrosine kinase also contribute to immune-mediated inflammatory in rheumatoid arthritis makes it likely that further development of orally administered protein kinase small molecule inhibitors for rheumatoid arthritis will occur in the near future.
Core tip: Signal transduction is a regulator of gene expression in cells. Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling is activated by pro-inflammatory cytokines which contributes to immune-mediated inflammation in rheumatoid arthritis. Medicinal chemistry was employed to develop JAK small molecule inhibitors for determining their clinical efficacy in active rheumatoid arthritis patients. Tofacitinib, a JAK small molecule inhibitor, is now generally used to treat moderate to severe rheumatoid arthritis patients who have not adequately responded to disease-modifying anti-rheumatic drugs or various biologic agents. The clinical efficacy of JAK small molecule inhibitors provides the impetus for future drug discovery targeted at other signal transduction pathways in rheumatoid arthritis.