基于蛋白降解靶向嵌合体的IRAK4降解剂的设计、合成及生物活性评价

Design,synthesis and biological evaluation of IRAK4 degraders based on proteolytic targeting chimera

目的 设计并合成具有抗肿瘤活性的白细胞介素-1受体相关激酶4(IRAK4)降解剂。方法 将IRAK4蛋白配体与E3连接酶配体经不同类型和长度的连接链进行连接,合成目标化合物,其结构经MS谱和~1H NMR谱确证。以大B细胞淋巴瘤细胞OCI-LY10为测试细胞株,对所合成的目标化合物进行体外抗肿瘤活性评价以及对IRAK4的降解测试。结果 合成了9个靶向IRAK4的降解剂,活性测试结果显示目标化合物均可抑制大B细胞淋巴瘤细胞OCI-LY10细胞增殖,其中化合物Ⅲ、Ⅶ、Ⅷ、Ⅸ对IRAK4有较强的降解活性,半数最大降解浓度(DC_(50))值在1~10 nmol·L^(-1)。结论 利用蛋白降解靶向嵌合体技术,通过对IRAK4的降解,实现对肿瘤细胞的增殖抑制,值得进一步研究。

Objective To design and synthesize interleukin-1 receptor-associated kinase 4(IRAK4)degraders with antitumor activity.Methods The target compounds were synthesized by ligating IRAK4 protein ligand and E3 ligase ligand with different types and lengths of linker chains.Their structures were confirmed by MS spectroscopy and 1H NMR spectroscopy.Large B-cell lymphoma cells OCI-LY10 were used as the test cell line,and the anti-tumor activity of the synthesized target compounds was evaluated in vitro and the degradation of IRAK4 was tested.Results Totally 9 degraders targeting IRAK4 were synthesized,and the activity test showed that the target compounds inhibited the proliferation of large B-cell lymphoma cells OCI-LY10 cells,among which compoundsⅢ,Ⅶ,Ⅷ,andⅨhad strong degradation against IRAK4,with the DC_(50) value at 1~10 nmol·L^(-1).Conclusion The use of protein degradation targeting chimera technology to inhibit the proliferation of tumor cells through the degradation of IRAK4 is worthy of further study.