A heterobifunctional IRAK4-targeting degrader impairs myddosome signaling in acute kidney injury and ameliorates kidney fibrosis

Heterobifunctional degraders emerge as a novel pharmacologic strategy to treat inflammatory conditions. Previous data have indicated that inflammatory signaling via the myddosome complex is critical for kidney injury and fibrosis development. Within the myddosome, modulation of interleukin-1 receptor associated kinase 4 (IRAK4) by small molecule kinase inhibitors has been shown to reduce fibrosis, but has limited anti-inflammatory effect. Here we used a novel strategy to abrogate IRAK4 by means of targeted ubiquitination triggering proteasomal degradation. We tested the antifibrotic and anti-inflammatory activity of the small molecule IRAK4 degrader KTX-545 in vitro and in vivo in a model of acute kidney injury. Our results indicated that incubation with degrader resulted in abrogation of IRAK4 protein levels, and reduced formation of myddosome complex in primary kidney fibrogenic cells. In human kidney organoids, IRAK4 degradation reduced both extracellular matrix deposition, as well as fibrogenic gene expression caused by tubular damage. Further, the treatment resulted in inhibition of NF-kB activation and downstream inflammatory cytokine expression. In vivo, KTX-545 showed increased efficacy compared to the small molecule IRAK4 kinase inhibitor CA-4948 in ameliorating fibrosis following ischemia/reperfusion injury. Collectively, our results indicate that targeted degradation of IRAK4 is a new promising therapeutic approach for the treatment of renal fibrosing disorders.