Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

Abstract

The serine/threonine kinase IL-1R–associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway. In mice, the compound inhibited cytokine production induced by injection of several different TLR agonists, including those for TLR2, TLR7, and TLR9. The compound also significantly suppressed skin inflammation induced by topical administration of the TLR7 agonist imiquimod. BMS-986126 demonstrated robust activity in the MRL/lpr and NZB/NZW models of lupus, inhibiting multiple pathogenic responses. In the MRL/lpr model, robust activity was observed with the combination of suboptimal doses of BMS-986126 and prednisolone, suggesting the potential for steroid sparing activity. BMS-986126 also demonstrated synergy with prednisolone in assays of TLR7- and TLR9-induced IFN target gene expression using human PBMCs. Lastly, BMS-986126 inhibited TLR7- and TLR9-dependent responses using cells derived from lupus patients, suggesting that inhibition of IRAK4 has the potential for therapeutic benefit in treating lupus.

IRAK4 kinase activity controls Toll-like receptor–induced inflammation through the transcription factor IRF5 in primary human monocytes

“…Our data show that IRAK4 controls the activation of IKK␤ to activate IRF5 but not NFB. Of note, and entirely consistent with our results, Dudhgaonkar et al (34) recently demonstrated inhibition of IKK␤ phosphorylation and cytokine release from TLR ligand stimulated human PBMC using an undisclosed highly potent and selective IRAK4 inhibitor, but did not present data regarding NFB. IKK␤ is thought to be the canonical activator of NFB, yet our data demonstrate that NFB is minimally affected with IRAK4 kinase inhibition in R848-treated human monocytes, as is phosphorylation and degradation of IB.…”

Cytokine production by activated plasmacytoid dendritic cells and natural killer cells is suppressed by an IRAK4 inhibitor

“…On the other hand, activation of autophagy favors plasmablast development, enabling expansion of self-reactive B cells in SLE, as well as type I IFN production by facilitating intracellular IC transport [ 41 , 42 ]. These observations merit further studies of the effects of I92 on different cell types, not least considering that IRAK4 inhibition ameliorates experimental murine lupus, suggesting a favorable effect also in human SLE [ 43 ]. Translating results of in-vitro studies of pharmaceutical compounds to potential drug effects in vivo has limitations.…”

Kinase inhibition in autoimmunity and inflammation

“…3 ) and, therefore, is a prime target candidate for the treatment of several inflammatory diseases 59 – 61 , 74 . Mutations in the kinase domain in IRAK4 that abrogate its activity protect mice in several inflammatory disease models, including septic shock 63 , 75 – 77 , SLE 78 – 80 , acute liver injury 81 , cardiovascular disease 82 and the APPPS1 Alzheimer disease model 83 .…”