Discovery Chemistry, Janssen Research & Development, Shanghai 201210, China.
Department of Biology, Janssen Research & Development, Shanghai 201210, China.
J Med Chem. 2021 Aug 12;64(15):10878-10889. doi: 10.1021/acs.jmedchem.1c00103. Epub 2021 Jul 19.
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, (), effectively degraded cellular IRAK1 protein with a DC of 3 nM in HBL-1 cells. Furthermore, 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.
MyD88 基因突变已被确定为激活 B 细胞样弥漫性大 B 细胞淋巴瘤（ABC DLBCL）中最常见的驱动突变之一。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，IRAK1 的支架功能，而不是其激酶活性，是肿瘤细胞存活所必需的。在此，我们介绍了一系列新型强效和选择性 IRAK1 降解剂的设计、合成和生物学评价。最有效的化合物之一（），在 HBL-1 细胞中有效降解细胞 IRAK1 蛋白，DC 值为 3 nM。此外，化合物 强烈抑制 IRAK1 下游信号通路，并在具有 MyD88 突变的 ABC DLBCL 细胞中表现出强烈的抗增殖作用。这项工作表明，IRAK1 降解剂有可能治疗依赖 IRAK1 支架功能的癌症。
