Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, PR China; Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, PR China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, PR China.
Eur J Med Chem. 2020 Mar 15;190:112092. doi: 10.1016/j.ejmech.2020.112092. Epub 2020 Jan 25.
Harboring MYD88 L265P mutation triggers tumors growth through the activation of NF-κB by interleukin-1 receptor associated kinase 4 (IRAK4) in diffuse large B-cell lymphoma (DLBCL), highlighting IRAK4 as a therapeutic target for tumors driven by aberrant MYD88 signaling. Herein, we report the design, synthesis, and structure-activity relationships of imidazo[1,2-b]pyridazines as potent IRAK4 inhibitors. The representative compound 5 exhibited excellent IRAK4 potency (IRAK4 IC = 1.3 nM) and favorable kinase selectivity profile. It demonstrated cellular selectivity for activated B cell-like (ABC) subtype DLBCL with MYD88 L265P mutation in cytotoxicity assay. The kinase inhibitory efficiency of compound 5 was further validated by Western blot analysis of phosphorylation of IRAK4 and downstream signaling in OCI-LY10 and TMD8 cells. Besides, combination of compound 5 and BTK inhibitor ibrutinib synergistically reduced the viability of TMD8 cells. These results indicated that compound 5 could be a promising IRAK4 inhibitor for the treatment of mutant MYD88 DLBCL.
MYD88 L265P 突变通过白细胞介素 1 受体相关激酶 4（IRAK4）激活 NF-κB 触发弥漫性大 B 细胞淋巴瘤（DLBCL）中的肿瘤生长，凸显了 IRAK4 作为异常 MYD88 信号驱动的肿瘤的治疗靶点。在此，我们报告了咪唑并[1,2-b]哒嗪作为有效 IRAK4 抑制剂的设计、合成和构效关系。代表性化合物 5 表现出优异的 IRAK4 活性（IRAK4 IC = 1.3 nM）和良好的激酶选择性特征。在细胞毒性测定中，它对携带 MYD88 L265P 突变的激活 B 细胞样（ABC）亚型 DLBCL 具有细胞选择性。Western blot 分析还进一步验证了化合物 5 对 IRAK4 磷酸化和 OCI-LY10 和 TMD8 细胞下游信号的抑制效率。此外，化合物 5 与 BTK 抑制剂依鲁替尼联合使用可协同降低 TMD8 细胞的活力。这些结果表明，化合物 5 可能是治疗突变型 MYD88 DLBCL 的一种有前途的 IRAK4 抑制剂。
