KTX-545 (KTX545) is a potent, selective IRAK4-targeting degrader with DC50 of 0.9 nM determined in in vitro assays with human monocytes.
IRAK4 is the only protein degraded of over 10,000 different proteins in human peripheral blood mononuclear cells (PBMCs) incubated with a concentration of KTX-545 ten-fold over its DC90.
KTX-545 specifically links the Cereblon (CRBN) domain binding the E3 ligase to IRAK4, induces ubiquitination and degradation by the 26S proteasome with IC50 of 60 nM (CRBN) and 11 nM (IRAK4).
KTX-545 induces impairment of myddosome formation and a significant reduction of NF-kB-driven gene expression in isolated primary mouse kSFCs.
KTX-545 significantly reduces the expression of the myofibroblast marker gene Acta2 encoding myofibroblast smooth muscle actin (Sma), the extracellular matrix protein encoding genes Col1a1, Fn1 and Fbn1 and the cytokines Tgfb and Ctgf.
KTX-545 shows increased efficacy compared to the small molecule IRAK4 kinase inhibitor CA-4948 in ameliorating fibrosis following ischemia/reperfusion injury.