设计、合成及 2,3-二氢苯并呋喃 IRAK4 抑制剂的药理学评价，用于治疗弥漫性大 B 细胞淋巴瘤。
Design, synthesis and pharmacological evaluation of 2,3-dihydrobenzofuran IRAK4 inhibitors for the treatment of diffuse large B-cell lymphoma.
机构信息
Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing, 210009, PR China.
Division of Antitumor Pharmacology, 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.
出版信息
Eur J Med Chem. 2023 Aug 5;256:115453. doi: 10.1016/j.ejmech.2023.115453. Epub 2023 May 5.
Interleukin-1 receptor associated kinase 4 (IRAK4) is a critical mediator of MYD88 L265P-induced NF-κB activation, indicating it is a promising therapeutic target for diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of 2,3-dihydrobenzofuran IRAK4 inhibitors through structure-based drug design. The representative compound 22 exhibited strong IRAK4 inhibitory potency (IRAK4 IC = 8.7 nM), favorable kinase selectivity and high antiproliferative activity against the MYD88 L265P DLBCL cell line (OCI-LY10 IC = 0.248 μM). Compound 22 also exhibited the ability to inhibit the activation of IRAK4 signaling pathway and induce apoptosis in MYD88 L265P DLBCL cell line. In combination with Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, 22 showed enhanced apoptosis-inducing effect and antiproliferative potency. The most advanced compound 22 in this inhibitor series holds promise for further development into efficacious and selective IRAK4 inhibitors for the treatment of DLBCL.
白细胞介素-1 受体相关激酶 4（IRAK4）是 MYD88 L265P 诱导 NF-κB 激活的关键介质，表明它是弥漫性大 B 细胞淋巴瘤（DLBCL）有前途的治疗靶点。本文通过基于结构的药物设计，报道了一系列 2,3-二氢苯并呋喃 IRAK4 抑制剂的发现。代表性化合物 22 表现出很强的 IRAK4 抑制活性（IRAK4 IC = 8.7 nM），对激酶具有良好的选择性，对 MYD88 L265P 弥漫性大 B 细胞淋巴瘤细胞系（OCI-LY10 IC = 0.248 μM）具有高增殖活性。化合物 22 还能够抑制 IRAK4 信号通路的激活，并诱导 MYD88 L265P 弥漫性大 B 细胞淋巴瘤细胞系凋亡。与布鲁顿酪氨酸激酶（BTK）抑制剂伊布替尼联合使用时，22 表现出增强的诱导凋亡作用和增殖抑制作用。该抑制剂系列中最先进的化合物 22 有望进一步开发成为治疗 DLBCL 的有效和选择性 IRAK4 抑制剂。
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