摘要Interleukin-1 receptor-associated kinase 4(IRAK4)is a pivotal enzyme in the Toll-like re-ceptor(TLR)/MYD88 dependent signaling pathway,which is highly activated in rheumatoid arthritis tis-sues and activated B cell-like diffuse large B-cell lymphoma(ABC-DLBCL).Inflammatory responses followed by IRAK4 activation promote B-cell proliferation and aggressiveness of lymphoma.Moreover,proviral integration site for Moloney murine leukemia virus 1(PIM1)functions as an anti-apoptotc ki-nase in propagation of ABC-DLBCL with ibrutinib resistance.We developed a dual IRAK4/PIM1 inhib-itor KIC-0101 that potently suppresses the NF-KB pathway and proinflammatory cytokine induction in vitro and in vivo.In rheumatoid arthritis mouse models,treatment with KIC-0101 significantly ameliorated cartilage damage and inflammation.KIC-0101 inhibited the nuclear translocation of NF-KB and activation of JAK/STAT pathway in ABC-DLBCLs.In addition,KIC-0101 exhibited an anti-tumor effect on ibrutinib-resistant cells by synergistic dual suppression of TLR/MYD88-mediated NF-KB pathway and PIM1 kinase.Our results suggest that KIC-0101 is a promising drug candidate for autoim-mune diseases and ibrutinib-resistant B-cell lymphomas.