Yuan Haibin, Gao Yue, Wang Peipei, Dong Xiaowu, Li Jia, Wang Chenxi, Che Jinxin, Zhou Yubo, Liu Tao
Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Zijingang Campus, Hangzhou, 310058, PR China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, PR China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, 528400, PR China.
Eur J Med Chem. 2025 Oct 15;296:117845. doi: 10.1016/j.ejmech.2025.117845. Epub 2025 Jun 13.
Starting with the lead compound L-1, a series of pyrrolo[2,3-d]pyrimidine derivatives were developed as FLT3/IRAK4 inhibitors through three rounds of rational structural optimization. Among them, HB-29 had the remarkable activity towards FLT3-WT (IC = 1.95 nM) and IRAK4 (IC = 53.72 nM), outperforming the positive control, CA-4948. Besides, it exhibited excellent activities in MV4-11, MOLM3, and BaF3 cells with varying FLT3-TKD and FLT3-ITD-TKD mutations, highlighting its potential to overcome acquired resistance. The toxicity of HB-29 to normal bone marrow cell line HS-5 is relatively low (SI > 2000). Mechanistic studies revealed that HB-29 inhibited FLT3 and IRAK4 pathways in a dose-dependent manner, promoting cell apoptosis. Notably, in the cytokine-induced cell model, HB-29 efficiently induced apoptosis, and while also enhancing SOD activity and reducing ROS accumulation, thereby demonstrating its potential to overcome adaptive resistance. Moreover, HB-29 demonstrated an acceptable bioavailability (F = 13.4 %). These findings confirm that FLT3/IRAK4 inhibitor is a promising strategy for the treatment of AML.
从先导化合物L-1开始，通过三轮合理的结构优化，开发了一系列吡咯并[2,3-d]嘧啶衍生物作为FLT3/IRAK4抑制剂。其中，HB-29对FLT3-WT（IC = 1.95 nM）和IRAK4（IC = 53.72 nM）具有显著活性，优于阳性对照CA-4948。此外，它在具有不同FLT3-TKD和FLT3-ITD-TKD突变的MV4-11、MOLM3和BaF3细胞中表现出优异的活性，突出了其克服获得性耐药的潜力。HB-29对正常骨髓细胞系HS-5的毒性相对较低（SI > 2000）。机制研究表明，HB-29以剂量依赖性方式抑制FLT3和IRAK4通路，促进细胞凋亡。值得注意的是，在细胞因子诱导的细胞模型中，HB-29有效地诱导凋亡，同时还增强了超氧化物歧化酶（SOD）活性并减少了活性氧（ROS）积累，从而证明了其克服适应性耐药的潜力。此外，HB-29表现出可接受的生物利用度（F = 13.4%）。这些发现证实，FLT3/IRAK4抑制剂是治疗急性髓系白血病（AML）的一种有前景的策略。
