Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

中文翻译：

---

LC-MI-3 的发现：一种有效的口服生物可利用的白细胞介素 1 受体相关激酶 4 降解剂，用于治疗炎症性疾病


Interleukin-1 受体相关激酶 4 (IRAK4) 是炎症相关疾病的一个有前景的治疗靶点。然而，由于 IRAK4 作为活性激酶和支架蛋白的双重作用，抑制 IRAK4 激酶活性可能会产生中等的抗炎功效。在此，我们报告了一种有效且选择性的 IRAK4 蛋白水解靶向嵌合分子的设计、合成和生物学评估，该分子消除了 IRAK4 支架功能。最有效的化合物 LC-MI-3 可有效降解细胞 IRAK4，半最大降解浓度为 47.3 nM。 LC-MI-3有效抑制下游核因子-κB信号传导的激活，发挥比传统激酶抑制剂更有效的药理作用。此外，与体内激酶抑制剂相比，LC-MI-3 在脂多糖和大肠杆菌诱导的急性和慢性炎症皮肤模型中发挥了显着的治疗效果。因此，LC-MI-3是替代靶向策略和先进药物开发中的候选IRAK4降解剂。