Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/ IRAK4 inhibitors
文献类型：期刊论文
| 作者 | Yuan, Haibin5; Gao, Yue3,4; Wang, Peipei4; Dong, Xiaowu5; Li, Jia3,4 ; Wang, Chenxi5; Che, Jinxin5; Zhou, Yubo3,4; Liu, Tao1,2,5
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2025-10-15 |
| 卷号 | 296页码:23 |
| 关键词 | AML FLT3/IRAK4 inhibitor Pyrrolo [2,3-d] pyrimidine Acquired resistance Adaptive resistance |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117845 |
| 通讯作者 | Che, Jinxin(chejx@zju.edu.cn) ; Zhou, Yubo(ybzhou@simm.ac.cn) ; Liu, Tao(lt601@zju.edu.cn) |
| 英文摘要 | 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 (IC50 = 1.95 nM) and IRAK4 (IC50 = 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. |
| WOS关键词 | ACUTE MYELOID-LEUKEMIA ; MUTATIONS |
| 资助项目 | National Natural Science Foundation of China[82273783] ; Zhejiang Provincial Natural Science Foundation of China[LZ21H300001] ; Guangdong High-level new R D Institute[2023000003] ; Guangdong High-level new R D Institute[2019B090904008] ; Zhongshan Science and Technology Bureau[CXTD2023009] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001513789900001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318621]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Che, Jinxin; Zhou, Yubo; Liu, Tao |
| 作者单位 | 1.Zhejiang Univ, Hangzhou Inst Innovat Med, Inst Drug Discovery & Design, Hangzhou 310058, Peoples R China 2.Zhejiang Univ, Natl Key Lab Adv Drug Delivery & Release Syst, Hangzhou 310058, Peoples R China 3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan 528400, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 5.Zhejiang Univ, Inst Drug Discovery & Design, Coll Pharmaceut Sci, Zijingang Campus, Hangzhou 310058, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yuan, Haibin,Gao, Yue,Wang, Peipei,et al. Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/ IRAK4 inhibitors[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,296:23. |
| APA | Yuan, Haibin.,Gao, Yue.,Wang, Peipei.,Dong, Xiaowu.,Li, Jia.,...&Liu, Tao.(2025).Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/ IRAK4 inhibitors.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,296,23. |
| MLA | Yuan, Haibin,et al."Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/ IRAK4 inhibitors".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 296(2025):23. |
入库方式： OAI收割
来源：上海药物研究所
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