Discovery of Novel, Potent, and Selective IRAK1 Inhibitors as Potential Therapeutics for Hepatocellular Carcinoma

Interleukin-1 receptor-associated kinase 1 (IRAK1) is a critical mediator of Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) signaling, and its aberrant activation is implicated in the pathogenesis of various cancers, including hepatocellular carcinoma (HCC). However, the development of clinical IRAK1 inhibitors has been hampered by a lack of sufficient selectivity over other kinases. Herein, we report the discovery of a novel IRAK1 inhibitor, <b>A34</b>, identified through structure-based virtual screening and structural optimization. <b>A34</b> potently inhibited IRAK1 with an IC₅₀ value of 10.6 nM and demonstrated exceptional selectivity over 215 other kinases, notably including IRAK4. Furthermore, <b>A34</b> demonstrated significant anti-HCC activity both <i>in vivo</i> and <i>in vitro</i>, making it a valuable chemical probe for IRAK1 and a potential lead candidate for the treatment of HCC.