IRAK4

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that functions as a key mediator in Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling pathways^[1][2]. Mechanistically, IRAK4 initiates myddosome formation by recruiting and activating IRAK1, facilitating downstream NF-κB and MAPK signaling^[2][3]. Compared with other IRAK family members, IRAK4 possesses both kinase activity and scaffolding functions, with its scaffold role being essential for myddosome assembly independent of catalytic activity^[2][3]. Dysregulation or overexpression of IRAK4 contributes to inflammatory, autoimmune, and oncogenic processes, including rheumatoid arthritis, myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML)^[1][4][5]. In MDS and AML, long isoforms of IRAK4 (IRAK4-L) produced by spliceosome mutations such as SF3B1 or U2AF1 retain maximal functional domains, driving constitutive NF-κB activation and sustaining leukemic stem cell function^[5][6][7]. Selective IRAK4 inhibitors, including DW18134, CA-4948, PF-06650833, and KME-0584, have demonstrated efficacy in preclinical models by reducing proinflammatory cytokines and suppressing leukemic progenitor proliferation^[8][9][10]. Dual inhibition of IRAK4 and IRAK1 enhances therapeutic outcomes, as IRAK1 compensatory activation can limit the efficacy of IRAK4-selective agents^[9]. Mechanistic studies also highlight that IRAK4 degraders, which eliminate both scaffolding and kinase functions, achieve broader suppression of TLR/IL-1R-induced NF-κB and p38 signaling compared with kinase inhibition alone^[3].