Jin Jiaming, Cui Zhenzhen, Lv Cheng, Peng Xuemei, Yan Zhiqi, Song Yi, Cao Yu, Zhou Wenyi, Wang Enpeng, Chen Xufan, Kang Di, Hu Lihong, Wang Junwei
Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
Bioorg Chem. 2023 Sep;138:106645. doi: 10.1016/j.bioorg.2023.106645. Epub 2023 Jun 2.
FLT3-ITD mutant has been extensively studied as a drug discovery target for acute myeloid leukemia. Based on our previous discovered FLT3 inhibitor (2), a series of urea group based indolone derivatives were designed, synthesized, and biological evaluated as novel FLT3 inhibitors for the treatment of FLT3-ITD positive AML. Among them, compound LC-3 exhibited potent inhibitory effects against FLT3 (IC = 8.4 nM) and significantly inhibited the proliferation of FLT3-ITD positive AML cells MV-4-11 (IC = 5.3 nM). In the cellular context, LC-3 strongly inhibited FLT3-mediated signaling pathways and induced cellular apoptosis by arresting cell cycle in G1 phase. In the in vivo studies, LC-3 significantly suppressed the tumor growth on MV-4-11 xenograft models (10 mg/kg/day, TGI = 92.16%) without exhibiting obvious toxicity. These results suggested that compound LC-3 might be a potential drug candidate for FLT3-ITD positive AML.
FLT3-ITD突变体作为急性髓系白血病的药物发现靶点已被广泛研究。基于我们之前发现的FLT3抑制剂（2），设计、合成了一系列基于脲基的吲哚酮衍生物，并对其作为治疗FLT3-ITD阳性急性髓系白血病的新型FLT3抑制剂进行了生物学评价。其中，化合物LC-3对FLT3表现出强效抑制作用（IC = 8.4 nM），并显著抑制FLT3-ITD阳性急性髓系白血病细胞MV-4-11的增殖（IC = 5.3 nM）。在细胞环境中，LC-3强烈抑制FLT3介导的信号通路，并通过使细胞周期停滞在G1期诱导细胞凋亡。在体内研究中，LC-3显著抑制MV-4-11异种移植模型上的肿瘤生长（10 mg/kg/天，TGI = 92.16%），且未表现出明显毒性。这些结果表明化合物LC-3可能是FLT3-ITD阳性急性髓系白血病的潜在候选药物。
