Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: IL-1R/TLR activation plays a central role in the pathophysiology of multiple autoimmune and inflammatory diseases driven by the IL-1 family of cytokines and by TLR ligands. Full signaling from IL-1Rs and TLRs through the Myddosome is dependent on both the kinase and scaffolding functions of Interleukin-1 receptor associated kinase 4 (IRAK4) (De Nardo et al. JBC 2018, De et al. JBC 2018). Therefore, hetero-bifunctional molecules that selectively target IRAK4 for degradation and elimination by the ubiquitin proteasome pathway have greatest potential to abrogate IL-1R/TLR signaling and shut down both the production of and response to TLR and IL-1 family cytokines.
Methods: Heterobifunctional degraders were designed to selectively target IRAK4 protein. Degradation selectivity was assessed in relevant human PBMC population by unbiased tandem mass tag proteomics. In vitro, PBMC flow cytometry and cytokine release assays were established to determine degradation potency (DC50) and inhibition of R848, LPS and IL-1β induced pro-inflammatory cytokines. IRAK4 degrader was dosed orally in the mouse monosodium urate (MSU) air pouch model of gouty arthritis. In vivo, degradation was measured in mouse spleen tissues by targeted mass spectrometry.
Results: Unbiased proteomics with a depth >10,000 proteins showed exclusive degradation of IRAK4 in human PBMCs. In vitro, selective IRAK4 degraders led to potent and greater than 90% degradation in both lymphocytes (DC50= 1.5nM) and monocytes (DC50=0.4nM). Pre-treatment with IRAK4 degraders achieved potent single digit nanomolar inhibition of R848, LPS and IL-1β induced pro-inflammatory cytokines (TNF-α, IL-6) and chemokines (CCL3). Importantly, IRAK4 degradation led to more effective inhibition of cytokine and chemokine induction compared to a selective IRAK4 kinase inhibitor. Oral administration of an IRAK4 degrader in the mouse MSU air pouch model led to dose-dependent IRAK4 degradation in spleen tissue and a marked decrease in neutrophil infiltration (p=0.002 unpaired t test, two-tailed).
Conclusion: Selective and potent targeted IRAK4 degradation led to marked inhibition of both TLR- and IL-1R-mediated pro-inflammatory cytokine and chemokine production. By removal of both scaffolding and kinase functions, IRAK4 degradation demonstrated greater activity compared to kinase inhibition alone across multiple TLR/IL-1R stimuli. Promising in vivo mouse data showed that oral administration of an IRAK4 degrader can be achieved and have an effect on TLR/IL-1β-driven inflammation in a gouty arthritis model. Together, these data show the potential for IRAK4 degraders to treat TLR/IL-1R-driven inflammatory and autoimmune diseases.
To cite this abstract in AMA style:Campbell V, Kelleher J, Chen J, Gollob J, Ji N, Klaus C, Loh C, mayo M, McDonald A, Rong H, Rusin S, Sharma K, Weiss M, Yuan K, Walker D, Zheng X, Slavin A, Mainolfi N. A First-in-class Selective and Potent IRAK4 Degrader Demonstrates Robust in Vitro and in Vivo Inhibition of TLR/IL-1R Activation and Inflammation [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-first-in-class-selective-and-potent-irak4-degrader-demonstrates-robust-in-vitro-and-in-vivo-inhibition-of-tlr-il-1r-activation-and-inflammation/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-first-in-class-selective-and-potent-irak4-degrader-demonstrates-robust-in-vitro-and-in-vivo-inhibition-of-tlr-il-1r-activation-and-inflammation/