Interleukin-1 receptor-associated kinase 4(IRAK4)is a key kinase downstream of the interleukin-1 receptor(IL-1R)and Toll-like receptors(TLRs)signaling pathway,whose overexpression and hyperactivation have been associa...Interleukin-1 receptor-associated kinase 4(IRAK4)is a key kinase downstream of the interleukin-1 receptor(IL-1R)and Toll-like receptors(TLRs)signaling pathway,whose overexpression and hyperactivation have been associated with several inflammatory diseases or cancer.Therefore,targeting IRAK4 has emerged as a promising therapeutic strategy.A range of potent and selective IRAK4 inhibitors and degraders based on draggability have been designed and developed.This article provides a comprehensive summary of the IRAK4 inhibitors and degraders that have been developed and discusses the challenges and opportunities for research in this area.展开更多
Interleukin-1 receptor-associated kinase 4(IRAK4),a key target with both enzymatic and non-enzymatic functions,plays a pivotal role in autoimmune diseases.Previous studies have demonstrated that proteolysis-targeting ...Interleukin-1 receptor-associated kinase 4(IRAK4),a key target with both enzymatic and non-enzymatic functions,plays a pivotal role in autoimmune diseases.Previous studies have demonstrated that proteolysis-targeting chimera(PROTAC)molecules targeting IRAK4 can effectively eliminate both its enzymatic and non-enzymatic functions,showing promising therapeutic potential.However,the development of highly potent,synthetically accessible IRAK4-targeting degraders remains a challenge.In this work,through three rounds of PROTAC library construction,screening,and optimization,we successfully identified a representative compound,LZ-07,which proved to be a highly potent degrader with a half-maximal degradation concentration(DC_(50))value of 1.14 nmol/L.Notably,compared with KT-474,LZ-07 demonstrated comparable degradation activity and superior inhibition of cytokine production,while featuring a simpler synthetic route with optimized IRAK4 and cereblon(CRBN)ligands.LZ-07-induced degradation of IRAK4 led to marked suppression of key cytokines,including interleukin-6(IL-6),IL-1β,tumor necrosis factor alpha(TNF-α),and IL-10.This study presents LZ-07 as a novel,highly efficient,and synthetically straightforward IRAK4-targeting degrader,offering a promising tool compound for the study of the potential treatment of autoimmune diseases.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82293684,82293680)the National Key R&D Program of China(No.2020YFA0908004)CAMS Innovation Fund for Medical Science of China(No.2022-I2M-1-014)。
文摘Interleukin-1 receptor-associated kinase 4(IRAK4)is a key kinase downstream of the interleukin-1 receptor(IL-1R)and Toll-like receptors(TLRs)signaling pathway,whose overexpression and hyperactivation have been associated with several inflammatory diseases or cancer.Therefore,targeting IRAK4 has emerged as a promising therapeutic strategy.A range of potent and selective IRAK4 inhibitors and degraders based on draggability have been designed and developed.This article provides a comprehensive summary of the IRAK4 inhibitors and degraders that have been developed and discusses the challenges and opportunities for research in this area.
基金supported by National Natural Science Foundation of China(Nos.82125034,82330115)National Key R&D Program of China(Nos.2021YFA1300200,2021YFA1302100)+1 种基金the Beijing Outstanding Young Scientist Program(No.JWZQ20240101007)Beijing Frontier Research Center for Biological Structure。
文摘Interleukin-1 receptor-associated kinase 4(IRAK4),a key target with both enzymatic and non-enzymatic functions,plays a pivotal role in autoimmune diseases.Previous studies have demonstrated that proteolysis-targeting chimera(PROTAC)molecules targeting IRAK4 can effectively eliminate both its enzymatic and non-enzymatic functions,showing promising therapeutic potential.However,the development of highly potent,synthetically accessible IRAK4-targeting degraders remains a challenge.In this work,through three rounds of PROTAC library construction,screening,and optimization,we successfully identified a representative compound,LZ-07,which proved to be a highly potent degrader with a half-maximal degradation concentration(DC_(50))value of 1.14 nmol/L.Notably,compared with KT-474,LZ-07 demonstrated comparable degradation activity and superior inhibition of cytokine production,while featuring a simpler synthetic route with optimized IRAK4 and cereblon(CRBN)ligands.LZ-07-induced degradation of IRAK4 led to marked suppression of key cytokines,including interleukin-6(IL-6),IL-1β,tumor necrosis factor alpha(TNF-α),and IL-10.This study presents LZ-07 as a novel,highly efficient,and synthetically straightforward IRAK4-targeting degrader,offering a promising tool compound for the study of the potential treatment of autoimmune diseases.
