Shi Kun, Hong Ye, Liu Huajing, Yang Xiaotian, Wang Fengzhen, Zhang Yanming
Clinical Medical College, Xuzhou Medical University, Xuzhou, China.
Department of Orthopedics, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, China.
Front Pharmacol. 2025 Feb 3;16:1511257. doi: 10.3389/fphar.2025.1511257. eCollection 2025.
Considering the essential role of FLT3-ITD mutations in the development of acute myeloid leukemia (AML), the research and development of FLT3 inhibitors hold significant therapeutic potential. In this study, we identified a novel, highly potent small molecule inhibitor, FLIN-4, targeting FLT3 through structure-based virtual screening. Notably, FLIN-4 showed exceptional inhibitory effects in kinase activity inhibition assays, exhibiting a potent inhibitory effect against FLT3 (IC = 1.07 ± 0.04 nM). This potency was significantly superior to that of the known positive inhibitor Midostaurin, showing approximately 27 times higher inhibitory potency. Molecular dynamics simulations have confirmed the stable interaction between FLIN-4 and FLT3. Furthermore, cytotoxicity assays revealed that FLIN-4 has significant anti-proliferative activity against the AML cell line MV4-11 (IC = 1.31 ± 0.06 nM). Overall, these data suggest that FLIN-4, as a potential therapeutic candidate for AML, is valuable for further research and development.
鉴于FLT3-ITD突变在急性髓系白血病（AML）发生发展中的关键作用，FLT3抑制剂的研发具有重大治疗潜力。在本研究中，我们通过基于结构的虚拟筛选鉴定出一种新型、高效的小分子抑制剂FLIN-4，其靶向FLT3。值得注意的是，FLIN-4在激酶活性抑制试验中表现出优异的抑制效果，对FLT3具有强效抑制作用（IC = 1.07 ± 0.04 nM）。这种效力显著优于已知的阳性抑制剂米哚妥林，抑制效力高出约27倍。分子动力学模拟证实了FLIN-4与FLT3之间的稳定相互作用。此外，细胞毒性试验表明，FLIN-4对AML细胞系MV4-11具有显著的抗增殖活性（IC = 1.31 ± 0.06 nM）。总体而言，这些数据表明，FLIN-4作为AML的潜在治疗候选药物，对进一步研发具有重要价值。
