Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzo-furan IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma

Interleukin-1 receptor associated kinase 4 (IRAK4) is a critical mediator of MYD88 L265P-induced NF-xB activation, indicating it is a promising therapeutic target for diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of 2,3-dihydrobenzofuran IRAK4 inhibitors through structure-based drug design. The representative compound 22 exhibited strong IRAK4 inhibitory potency (IRAK4 IC50 = 8.7 nM), favorable kinase selectivity and high antiproliferative activity against the MYD88 L265P DLBCL cell line (OCI-LY10 IC50 = 0.248 mu M). Compound 22 also exhibited the ability to inhibit the activation of IRAK4 signaling pathway and induce apoptosis in MYD88 L265P DLBCL cell line. In combination with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, 22 showed enhanced apoptosis-inducing effect and antiproliferative potency. The most advanced compound 22 in this inhibitor series holds promise for further development into efficacious and selective IRAK4 inhibitors for the treatment of DLBCL.

Automated summary

A series of 2,3-dihydrobenzofuran IRAK4 inhibitors were discovered through structure-based drug design. Compound 22 exhibited strong IRAK4 inhibitory potency and high antiproliferative activity against MYD88 L265P DLBCL cell line. Compound 22 also showed the ability to inhibit IRAK4 signaling pathway activation and induce apoptosis in MYD88 L265P DLBCL cell line.