2. Academic Validation
  3. Machine learning-aided design, synthesis and biological evaluation of novel 4-(imidazo[1,2-a]pyridine-3‑carbonyl) phenyl urea derivatives as potent FLT3 inhibitors

Machine learning-aided design, synthesis and biological evaluation of novel 4-(imidazo[1,2-a]pyridine-3‑carbonyl) phenyl urea derivatives as potent FLT3 inhibitors

  • Bioorg Chem. 2025 Sep:164:108912. doi: 10.1016/j.bioorg.2025.108912.
Qiang Huang 1,  Lvjia Wu 2,  Jiangdong Li 3,  Yongxin Lou 4,  Xin Jin 2,  Chenxi Wang 5,  Xiaoran Cao 5,  Xianheng Wang 2,  Lei Zhu 2,  Qianlu Xing 6,  Xiaojuan Ma 7,  Yihuan Zhao 8,  Changkuo Zhao 9
Affiliations

Affiliations

  • 1 School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.. Electronic address: huangqiang65@sina.com.
  • 2 School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.
  • 3 Pengshui Miao and Tujia Autonomous County Center for Disease Control and Prevention, Pengshui, Chongqing 409600, China.
  • 4 School of Preclinical Medicine, Zunyi Medical University, Zunyi, Guizhou 563006, China.
  • 5 The First Clinical Institute, Zunyi Medical University, Zunyi, Guizhou 563000, China.
  • 6 Department of Pediatric, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, China.
  • 7 School of Public Health, Zunyi Medical University, Zunyi, Guizhou 563000, China.
  • 8 School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.. Electronic address: zyhws@zmu.edu.cn.
  • 9 School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.. Electronic address: zck7103@hotmail.com.
PMID: 40876224 DOI: 10.1016/j.bioorg.2025.108912
Abstract

FLT3 protein kinase is a promising target for the treatment of acute myeloid leukemia (AML), and the development of this kinase inhibitor is highly desirable to overcome FLT3-positive AML. Herein, the bioactive predictions and screening were conducted based on our previous machine learning model in this work. Using ZY06 as a candidate, the design, synthesis and biological evaluation of a series of 4-(imidazo[1,2-a]pyridine-3‑carbonyl) phenyl urea derivatives as novel FLT3 inhibitors were systematically investigated. These compounds exhibited excellent inhibitory potency towards FLT3-ITD kinase, and moderate to potent antiproliferative activities against MV4-11 cells. The compound ZY12 displayed good selectivity to Other kinases and excellent bioactivity in vitro, and concentration-dependently induced cycle arrest of MV4-11 cells. Moreover, ZY12 could significantly block the phosphorylation of FLT3 and its downstream signal pathways, such as Akt and ERK, and exhibit good safety in vivo, which serve as a lead molecule for developing novel FLT3 inhibitors against AML.

Keywords

Acute myeloid leukemia; Antitumor; FLT3; Inhibitor; Machine learning.

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