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Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-07-19 , DOI: 10.1021/acs.jmedchem.1c00103
Liqiang Fu 1 , Jing Zhang 2 , Bin Shen 2 , Linglong Kong 1 , Yingtao Liu 1 , Wangyang Tu 1 , Wenqian Wang 2 , Xin Cai 3 , Xiaotao Wang 3 , Na Cheng 2 , Mingxuan Xia 2 , Tianyuan Zhou 2 , Qian Liu 1 , Yanping Xu 1 , Jennifer Yang 2 , Paul Gavine 2 , Ulrike Philippar 4 , Ricardo Attar 5 , James P Edwards 6 , Jennifer D Venable 6 , Xuedong Dai 1, 7
Affiliation  

MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.

中文翻译:

发现高效和选择性的 IRAK1 降解剂来探测 ABC DLBCL 中 IRAK1 的支架功能

MyD88 基因突变已被确定为活化 B 细胞样弥漫性大 B 细胞淋巴瘤 (ABC DLBCL) 中最普遍的驱动突变之一。已发表的文献表明,白细胞介素 1 受体相关激酶 1 (IRAK1) 是携带 MyD88 突变的 ABC DLBCL 的必需基因。重要的是,肿瘤细胞存活需要 IRAK1 的支架功能,而不是其激酶活性。在此,我们展示了我们对一系列新型强效选择性 IRAK1 降解剂的设计、合成和生物学评估。最有效的化合物之一,Degrader-3 ( JNJ-1013 ),在 HBL-1 细胞中以 3 nM的 DC 50有效降解细胞 IRAK1 蛋白。此外,JNJ-1013有效抑制 IRAK1 下游信号通路,并在 MyD88 突变的 ABC DLBCL 细胞中显示出强烈的抗增殖作用。这项工作表明 IRAK1 降解剂具有治疗依赖于 IRAK1 支架功能的癌症的潜力。
更新日期:2021-08-12
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