2. Academic Validation
  3. Identification of 2,4-disubstitued pyridine derivatives as potent FMS-like tyrosine receptor kinase 3 (FLT3) inhibitors

Identification of 2,4-disubstitued pyridine derivatives as potent FMS-like tyrosine receptor kinase 3 (FLT3) inhibitors

  • Bioorg Chem. 2025 Dec:167:109229. doi: 10.1016/j.bioorg.2025.109229.
Zhongyuan Wang 1,  Xinfu Liu 2,  Youli Hou 3,  Dongdong Cao 4,  Shiyu Hu 2,  Lihong He 3,  Yiwei Zhang 5,  Dongsheng Zhao 3,  Rui Chen 3,  Wenzhang Chen 3,  Aihong Li 6,  Weiwei Ouyang 7,  Weike Liao 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang 550002, China.
  • 2 Department of Hematology and Oncology, The Affiliated Shaoyang Hospital, Hengyang Medical School, University of South China (Shaoyang Central Hospital), Shaoyang 422000, China.
  • 3 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China.
  • 4 Department of Oncology, Affiliated Hospital of Guizhou Medical University and Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550001, China.
  • 5 Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 6 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China; Department of Nuclear Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563003, China. Electronic address: liaihongzmu@126.com.
  • 7 Department of Oncology, Affiliated Hospital of Guizhou Medical University and Affiliated Cancer Hospital of Guizhou Medical University, Guiyang, 550001, China. Electronic address: ouyangww103173@163.com.
  • 8 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang 550004, China. Electronic address: liaoweike2009@126.com.
PMID: 41242039 DOI: 10.1016/j.bioorg.2025.109229
Abstract

Accumulating evidence has shown that FMS-like tyrosine receptor kinase 3 (FLT3) activity plays a critical role in a substantial proportion of patients diagnosed with acute myeloid leukemia (AML), making it a potential molecular target for therapeutic intervention in AML treatment. Herein, a series of 2,4-disubstitued pyridine analogs, originating from the lead entity Liao-12y, were designed and synthesized. The most promising compound 6z, displayed single-digit nanomolar IC50 values against FLT3-ITD in both enzymatic and cellular assays, with selectivity over both FLT3 WT (32-fold) and c-Kit (180-fold) transformed BaF3 cells. Moreover, 6z suppressed the proliferation of FLT3-ITD driven MOLM-13 cells by blocking FLT3 phosphorylation and its downstream cascades (Akt, STAT5, and ERK), leading to cell cycle arrest and induction of Apoptosis. In in vivo pharmacokinetic (PK) studies, 6z displayed suitable intravenous PK parameters but suboptimal oral PK parameters. Overall, compound 6z holds potential as a robust lead compound for further advancement of therapeutic remedies for AML.

Keywords

2,4-disubstitued pyridine; AML; Antitumor activity; FLT3-ITD.

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