Kinase inhibitors in the treatment of immune-mediated disease

Abstract

Protein kinases are fundamental components of diverse signaling pathways, including immune cells. Their essential functions have made them effective therapeutic targets. Initially, the expectation was that a high degree of selectivity would be critical; however, with time, the use of "multikinase" inhibitors has expanded. Moreover, the spectrum of diseases in which kinase inhibitors are used has also expanded to include not only malignancies but also immune-mediated diseases. At present, thirteen kinase inhibitors have been approved in the United States, all for oncologic indications. However, there are a growing number of molecules, including several Janus kinase inhibitors, that are being tested in clinical trials for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel diseases. It appears likely that this new class of immunomodulatory drugs will have a major impact on the treatment of immune-mediated diseases in the near future.

Figure 1.. Proximal signaling pathways upon stimulation of immune receptors in B and T cells

Type I and II cytokine receptors associate with Janus kinases (Jaks). Cytokine binding activates Jaks, which then phosphorylate cytokine receptors allowing STAT (signal transducer and activator of transcription) DNA-binding proteins to attach to receptors and become phosphorylated. STAT activation leads to their dimerization and translocation to the nucleus where they regulate gene expression. Targets along the signal transduction pathway, including specific kinase inhibitors, are shown (left). In B cells, antigen ligation leads to activation of three main protein tyrosine kinases (PTKs) — the Src-family kinases Lyn, Syk and the TEC-family kinase Btk. Syk phosphorylates adaptor protein BLNK and, along with Btk, activates PLC γ. Activation of PLC γ leads to the release of intracellular Ca²⁺ and activation of protein kinase C (PKC), which activate mitogen-activated protein kinases (MAPKs). The MAPK cascade activates transcription factors nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT), allowing gene regulation (right). Abbreviations: BLNK: B cell linker protein; MAPK, mitogen-activated protein kinase; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κB; PLC γ, Phospholipase γ; PIP3K, phosphatidylinositol triphosphate kinase; PKC, protein kinase C; STAT, signal transducer and activator of transcription; Syk: Spleen tyrosine kinase; DAG, diacylglycerol; IP3, inositol 1,4,5-triphosphate.