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.
- 1. School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.. Electronic address: [email protected].
- 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: [email protected].
- 9. School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563000, China.. Electronic address: [email protected].
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.