Kymera Therapeutics, 500 N. Beacon Street, Fourth Floor, Watertown, Massachusetts 02472, United States.
J Med Chem. 2024 Oct 24;67(20):18022-18037. doi: 10.1021/acs.jmedchem.4c01305. Epub 2024 Aug 16.
Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential mediator of the IL-1R and TLR signaling pathways, both of which have been implicated in multiple autoimmune conditions. Hence, blocking the activity of IRAK4 represents an attractive approach for the treatment of autoimmune diseases. The activity of this serine/threonine kinase is dependent on its kinase and scaffolding activities; thus, degradation represents a potentially superior approach to inhibition. Herein, we detail the exploration of structure-activity relationships that ultimately led to the identification of KT-474, a potent, selective, and orally bioavailable heterobifunctional IRAK4 degrader. This represents the first heterobifunctional degrader evaluated in a nononcology indication and dosed to healthy human volunteers. This molecule successfully completed phase I studies in healthy adult volunteers and patients with atopic dermatitis or hidradenitis suppurativa. Phase II clinical trials in both of these indications have been initiated.
白细胞介素-1 受体相关激酶 4（IRAK4）是 IL-1R 和 TLR 信号通路的重要介质，这两种信号通路都与多种自身免疫性疾病有关。因此，阻断 IRAK4 的活性是治疗自身免疫性疾病的一种有吸引力的方法。这种丝氨酸/苏氨酸激酶的活性依赖于其激酶和支架活性；因此，降解是一种潜在的优于抑制的方法。本文详细介绍了结构-活性关系的探索，最终确定了 KT-474，一种有效的、选择性的、口服生物可利用的异双功能 IRAK4 降解剂。这是第一个在非肿瘤适应症中评估的异双功能降解剂，并在健康志愿者中进行了剂量测定。该分子已成功完成了健康成年志愿者和特应性皮炎或化脓性汗腺炎患者的 I 期研究。这两种适应症的 II 期临床试验已经启动。
