2. Academic Validation
  3. Design, synthesis, and biological evaluation of a series of indolone derivatives as novel FLT3 inhibitors for the treatment of acute myeloid leukemia

Design, synthesis, and biological evaluation of a series of indolone derivatives as novel FLT3 inhibitors for the treatment of acute myeloid leukemia

  • Bioorg Chem. 2023 Sep:138:106645. doi: 10.1016/j.bioorg.2023.106645.
Jiaming Jin 1,  Zhenzhen Cui 1,  Cheng Lv 1,  Xuemei Peng 1,  Zhiqi Yan 1,  Yi Song 1,  Yu Cao 1,  Wenyi Zhou 1,  Enpeng Wang 1,  Xufan Chen 1,  Di Kang 2,  Lihong Hu 3,  Junwei Wang 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
  • 2 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China. Electronic address: kangdi@njucm.edu.cn.
  • 3 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China. Electronic address: lhhu@njucm.edu.cn.
  • 4 Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China. Electronic address: jwwang@njucm.edu.cn.
PMID: 37327602 DOI: 10.1016/j.bioorg.2023.106645
Abstract

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 (IC50 = 8.4 nM) and significantly inhibited the proliferation of FLT3-ITD positive AML cells MV-4-11 (IC50 = 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.

Keywords

AML; FLT3 inhibitors; FLT3-ITD; Indolone derivatives.

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