2. Academic Validation
  3. Design, synthesis and biological evaluation of 8-phenylquinazolin-2-amine derivatives as FLT3 covalent inhibitors targeting cysteine 828 in the ATP pocket

Design, synthesis and biological evaluation of 8-phenylquinazolin-2-amine derivatives as FLT3 covalent inhibitors targeting cysteine 828 in the ATP pocket

  • Eur J Med Chem. 2026 Jan 5:301:118212. doi: 10.1016/j.ejmech.2025.118212.
Wei Wei 1,  Zuli Hu 2,  Jiuyu Gao 2,  Tianqiong Yang 2,  Qi Zhang 2,  Kaiyan Xu 3,  Chongmin Qin 3,  Lin Yue 2,  Ningyu Wang 3,  Yu Cao 2,  Luoting Yu 4,  Zhihao Liu 5
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610041, China.
  • 2 Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 611756, China.
  • 4 Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Children's Medicine Key Laboratory of Sichuan Province, Sichuan University, Chengdu, 610041, China. Electronic address: yuluot@scu.edu.cn.
  • 5 Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: liuzhihao@scu.edu.cn.
PMID: 41056821 DOI: 10.1016/j.ejmech.2025.118212
Abstract

Targeting oncogenic activating mutations of Fms-Like tyrosine kinase 3 (FLT3) has constituted a promising therapy for acute myeloid leukemia (AML). However, rapid development of resistance has significantly compromised clinical efficacy and therapeutic durability of FLT3 inhibitors. Covalent inhibitors have shown impressive potential in overcoming drug resistance. Herein, we designed and synthesized a series of 8-phenylquinazolin-2-amine derivatives as FLT3 covalent inhibitors targeting cysteine 828. Among them, 4k demonstrated potent and selective inhibitory activities against FLT3-ITD positive AML cells and BaF3 cells harboring drug-resistant FLT3-ITD secondary mutations, including BaF3-FLT3-ITD-D835V/I. Biochemical and mass spectrometry analyses confirmed that 4k covalently bound to the Cys828 in the ATP pocket of FLT3. 4k also inhibited the phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and Apoptosis. Furthermore, 4k, with an oral bioavailability of 12.48%, effectively suppressed tumor growth in a MV4-11 xenograft model without obvious toxicity. Taken together, 4k represents a novel covalent inhibitor targeting Cys828 of FLT3 kinase for targeted therapy of AML.

Keywords

Acute myeloid leukemia; Covalent inhibitor; FLT3; Structure–activity relationship.

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