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, , identified through structure-based virtual screening and structural optimization. potently inhibited IRAK1 with an IC value of 10.6 nM and demonstrated exceptional selectivity over 215 other kinases, notably including IRAK4. Furthermore, demonstrated significant anti-HCC activity both and , making it a valuable chemical probe for IRAK1 and a potential lead candidate for the treatment of HCC.