A Multitude of Kinases—Which are the Best Targets in Treating Rheumatoid Arthritis?

Abstract

Synopsis Small-molecule kinase inhibitors are increasingly taking center stage in the quest for new drugs for the treatment of rheumatoid arthritis (RA). By targeting kinases, many of which orchestrate multiple signaling pathways, small-molecule inhibitors can exert potent anti-inflammatory and immunomodulatory effects. The success of small-molecule kinase inhibitors in the treatment of cancer, coupled with greater insight into inflammatory and immune signaling, has spurred efforts to identify kinases that could be targeted for the treatment of chronic inflammatory disorders such as RA. Several kinases have been convincingly implicated in the pathogenesis of RA, and many kinase inhibitors have proven efficacious in the treatment of inflammatory arthritis in animals; but few kinase inhibitors have so far been tested in RA clinical trials. Here we discuss the challenges and progress in the pursuit of small-molecule kinase inhibitors for RA, including the lessons learnt from the failure of erstwhile front-runner inhibitors and the tentative promise of inhibitors making their debut on the RA stage.

Clinical pharmacology of tocilizumab for the treatment of patients with rheumatoid arthritis

“…Small-molecule tyrosine kinases are among a new class of oral medications for RA currently in clinical trials. The Janus kinase (JAK) family is involved in both innate and adaptive immune responses and plays a key role in lymphocyte activation, function and proliferation [15,16]. Inhibitors of this family have demonstrated efficacy in Phase II clinical trials and one of these, tasocitinib (a JAK3 inhibitor), is currently in Phase III clinical trials [17].…”

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis

“…As an example, sunitinib is a multitargeted tyroxine kinase inhibitor. Dose-dependent off-target inhibition of the multitargeted tyroxine kinase inhibitor PK sunitinib contributes to its cardiotoxicity 22 23. Kinome-wide profiling has emerged as an important strategy in compound safety.…”

Inhibition of Toll-Like Receptor-Mediated Inflammation In Vitro and In Vivo by a Novel Benzoxaborole

“…The association of TLR signaling with these diseases promotes sustained efforts to develop novel drugs to block these pathways for a variety of disease indications. Attempts have been directed toward interfering with the association of TLRs with ligands or intracellular adaptor molecules (Hennessy et al, 2010;Loiarro et al, 2010), inhibiting the activation of critical kinases in TLR cascades (O'Neill, 2003;Lindstrom and Robinson, 2010) and blocking the functions of inflammatory cytokines (Kopf et al, 2010). Antagonists of TLRs and specific kinase inhibitors are either dx.doi.org/10.1124/jpet.112.200030. s This article has supplemental material available at jpet.aspetjournals.org.…”

“…in preclinical development or at various stages of clinical trials (Hennessy et al, 2010;Lindstrom and Robinson, 2010). Targeting cytokines, such as TNF-a, IL-1b, IL-6, and IL-23 with biologics, has proven beneficial and applied in clinical practice for different diseases (Kopf et al, 2010).…”