2. Academic Validation
  3. Discovery of pyridine-based derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia

Discovery of pyridine-based derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia

  • Eur J Med Chem. 2025 Feb 5:283:117173. doi: 10.1016/j.ejmech.2024.117173.
Beijing Chen 1,  Zhongyuan Wang 2,  Qi Chen 2,  Ying Zhang 1,  Shengfei Wu 1,  Yu Zhang 1,  Aihong Li 1,  Weiwei Ouyang 3,  Lijie Sima 4,  Xiaoxu Li 3,  Dongsheng Zhao 1,  Bilan Luo 5,  Jianta Wang 1,  Lei Tang 6,  Xiaoming Su 7,  Weike Liao 8
Affiliations

Affiliations

  • 1 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China.
  • 2 Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
  • 3 Department of Oncology, The Affiliated Hospital of Guizhou Medical University and Cancer Hospital of Guizhou Medical University, Guiyang, 550001, China.
  • 4 Department of Radiation Oncology, The Ninth Medical Center of Chinese PLA General Hospital, Beijing, 100101, China.
  • 5 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
  • 6 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China. Electronic address: tlei1974@gmc.edu.cn.
  • 7 Department of Radiation Oncology, The Ninth Medical Center of Chinese PLA General Hospital, Beijing, 100101, China. Electronic address: smallcatsxm2022@163.com.
  • 8 Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, 550004, China. Electronic address: liaoweike2009@126.com.
PMID: 39705732 DOI: 10.1016/j.ejmech.2024.117173
Abstract

FMS-like tyrosine receptor kinase 3 (FLT3) mutations, the most common genetic alterations found in acute myeloid leukemia (AML) patients, have been pursued as an ideal drug discovery target for the AML therapy. Taking compound 2 as lead, a series of pyridine derivatives bearing 1,2,3-triazole moiety were rationally designed and synthesized. The bioassays confirmed that these derivatives exerted potent antileukemia effects, and compound 12y was found to be the most potent one. 12y displayed double-digital nanomolar inhibitory activities against FLT3-ITD and FLT3-ITD driven human AML MOLM-13 cells as well as high selectivity over FLT3-ITD non-addicted cell lines. In addition, kinase profiling versus over 51 kinases demonstrated that 12y was potent against FLT3-ITD and VEGFR2/KDR/Flk-1. Moreover, treatment of MOLM-13 cells with 12y resulted in downregulated phosphorylation levels of FLT3 and STAT5, as well as cell cycle arrest and Apoptosis. With the acceptable oral bioavailability of 19.2 % in SD rats, 12y prolonged the survival rate of NSG mice dose-dependently in MOLM-13 inoculated xenograft model without obvious toxicity. Overall, this study might provide a new insight for the development of novel FLT3 inhibitors.

Keywords

Acute myeloid leukemia; FLT3; Kinase inhibitor.

Figures
Products