Nunes Joao, McGonagle Grant A, Eden Jessica, Kiritharan Girieshanie, Touzet Megane, Lewell Xiao, Emery John, Eidam Hilary, Harling John D, Anderson Niall A
Protein Degradation Discovery Performance Unit, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
GlaxoSmithKline, King of Prussia, Pennsylvania 19406, United States.
ACS Med Chem Lett. 2019 Jun 14;10(7):1081-1085. doi: 10.1021/acsmedchemlett.9b00219. eCollection 2019 Jul 11.
Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) is a key mediator of innate immunity. IRAK4 overactivation is linked with several autoimmune diseases. To date, many IRAK4 inhibitors have been developed to block the protein's kinase activity with the most advanced reaching Phase II clinical trials. Nevertheless, several reports suggest kinase activity is not disease-relevant in certain cell types, so removing scaffolding signaling in addition to IRAK4 kinase activity may offer a better therapeutic outcome. Herein, we describe the design and synthesis of an IRAK4 Proteolysis Targeted Chimera (PROTAC). We show that IRAK4 degradation induced by compound leads to the inhibition of multiple cytokines in PBMCs. However, in IL-1β stimulated human dermal fibroblasts, inhibition of IL-6 and TNF-α release was not observed despite IRAK4 degradation. Nonetheless, the possibility of targeting both IRAK4 kinase and scaffolding function could potentially lead to new therapeutic opportunities to treat autoimmune, inflammatory, and oncological diseases.
白细胞介素-1受体相关激酶4（IRAK4）是先天性免疫的关键介质。IRAK4过度激活与多种自身免疫性疾病有关。迄今为止，已经开发了许多IRAK4抑制剂来阻断该蛋白的激酶活性，其中最先进的已进入II期临床试验。然而，一些报告表明，激酶活性在某些细胞类型中与疾病无关，因此除了IRAK4激酶活性外，去除支架信号可能会带来更好的治疗效果。在此，我们描述了一种IRAK4蛋白酶靶向嵌合体（PROTAC）的设计与合成。我们表明，化合物诱导的IRAK4降解导致外周血单核细胞中多种细胞因子的抑制。然而，在IL-1β刺激的人皮肤成纤维细胞中，尽管IRAK4降解，但未观察到IL-6和TNF-α释放的抑制。尽管如此，靶向IRAK4激酶和支架功能的可能性可能会为治疗自身免疫性、炎症性和肿瘤性疾病带来新的治疗机会。
