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, A34, identified
through structure-based virtual screening and structural optimization. A34 potently inhibited IRAK1 with an IC50 value
of 10.6 nM and demonstrated exceptional selectivity over 215 other
kinases, notably including IRAK4. Furthermore, A34 demonstrated
significant anti-HCC activity both in vivo and in vitro, making it a valuable chemical probe for IRAK1
and a potential lead candidate for the treatment of HCC.