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
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
目的：通过研究尿酸性肾病动物模型中白介素-1（IL-1）β和白介素-1受体相关激酶4（IRAK-4）表达的意义,了解IL-1β信号通路在尿酸性肾病中的作用。方法：Wistar大鼠54只随机分为高尿酸血症组30只、正常组24只,制备尿酸性肾病大鼠模型,...目的：通过研究尿酸性肾病动物模型中白介素-1（IL-1）β和白介素-1受体相关激酶4（IRAK-4）表达的意义,了解IL-1β信号通路在尿酸性肾病中的作用。方法：Wistar大鼠54只随机分为高尿酸血症组30只、正常组24只,制备尿酸性肾病大鼠模型,检测尿酸（UA）、尿素氮（BUN）、肌酐（CR）及肌酐清除率（Ccr）、24 h尿微量白蛋白（m A1b）;取肾脏组织行HE染色,观察形态学变化;免疫组化测定IL-1β的表达;荧光定量PCR检测IRAK-4 m RNA的水平。结果：高尿酸组2、4、6周时IL-1β的表达均增加,免疫组化评分（IHS）均明显升高（P〈0.01）;高尿酸血症组较正常组IRAK-4 m RNA在2、4、6周时均出现表达上调,4~6周IRAK-4 m RNA表达明显增加,与正常组比较有显著性差异（P〈0.01）。结论：IL-1β、IRAK-4参与了尿酸性肾病炎症反应的过程,可能为尿酸性肾病治疗提供新的可能。展开更多
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.
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.
文摘目的：通过研究尿酸性肾病动物模型中白介素-1（IL-1）β和白介素-1受体相关激酶4（IRAK-4）表达的意义,了解IL-1β信号通路在尿酸性肾病中的作用。方法：Wistar大鼠54只随机分为高尿酸血症组30只、正常组24只,制备尿酸性肾病大鼠模型,检测尿酸（UA）、尿素氮（BUN）、肌酐（CR）及肌酐清除率（Ccr）、24 h尿微量白蛋白（m A1b）;取肾脏组织行HE染色,观察形态学变化;免疫组化测定IL-1β的表达;荧光定量PCR检测IRAK-4 m RNA的水平。结果：高尿酸组2、4、6周时IL-1β的表达均增加,免疫组化评分（IHS）均明显升高（P〈0.01）;高尿酸血症组较正常组IRAK-4 m RNA在2、4、6周时均出现表达上调,4~6周IRAK-4 m RNA表达明显增加,与正常组比较有显著性差异（P〈0.01）。结论：IL-1β、IRAK-4参与了尿酸性肾病炎症反应的过程,可能为尿酸性肾病治疗提供新的可能。
