Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases,Journal of Medicinal Chemistry

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Discovery of KT-474─a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-16 , DOI: 10.1021/acs.jmedchem.4c01305
Xiaozhang Zheng ₁ , Nan Ji ₁ , Veronica Campbell ₁ , Anthony Slavin ₁ , Xiao Zhu ₁ , Dapeng Chen ₁ , Haojing Rong ₁ , Brad Enerson ₁ , Michele Mayo ₁ , Kirti Sharma ₁ , Chris M Browne ₁ , Christine R Klaus ₁ , Haoran Li ₁ , Ginny Massa ₁ , Alice A McDonald ₁ , Yatao Shi ₁ , Mike Sintchak ₁ , Stephanie Skouras ₁ , Dirk M Walther ₁ , Karen Yuan ₁ , Yi Zhang ₁ , Joe Kelleher ₁ , Guang Liu ₁ , Xinbo Luo ₁ , Nello Mainolfi ₁ , Matthew M Weiss ₁

Affiliation

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.

中文翻译：

KT-474 的发现——一种用于治疗自身免疫性疾病的强效、选择性和口服生物可利用的 IRAK4 降解剂

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，这两者都与多种自身免疫性疾病有关。因此，阻断 IRAK4 的活性代表了治疗自身免疫性疾病的一种有吸引力的方法。这种丝氨酸/苏氨酸激酶的活性取决于其激酶和支架活性;因此，降解代表了一种潜在的优越抑制方法。在本文中，我们详细介绍了对结构-活性关系的探索，最终导致鉴定了 KT-474，KT-474 是一种有效的、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并给药给健康人类志愿者的异双功能降解剂。该分子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。这两个适应症的 II 期临床试验都已启动。

更新日期：2024-08-16

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