2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel Fms-Like Tyrosine Kinase 3/VEGFR2/Histone Deacetylase Inhibitors for the Treatment of Acute Myeloid Leukemia

Design, Synthesis, and Biological Evaluation of Novel Fms-Like Tyrosine Kinase 3/VEGFR2/Histone Deacetylase Inhibitors for the Treatment of Acute Myeloid Leukemia

  • J Med Chem. 2025 Feb 19. doi: 10.1021/acs.jmedchem.4c03084.
Hua Tian 1 2 3,  Yichen Liu 1 3,  Songwen Lin 1 2 3,  Jialing Deng 1 3,  Qinghua Zhang 1 2 3,  Feng Hao 4,  Yao Tang 4,  Tianning Xiong 1 2 3,  Kehui Zhang 1 2 3,  Ge Shi 1 2 3,  Lijun Luo 5,  Shouguo Peng 1 2 3,  Li Sheng 5,  Ming Ji 1 3,  Heng Xu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 4 Kyinno Biotechnology Co., Ltd, F2 Building, Yizhuang Biomedical Park, No. 88, Kechuang Six Street, BDA, Beijing 101111, China.
  • 5 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 39970471 DOI: 10.1021/acs.jmedchem.4c03084
Abstract

The concurrent targeting of Fms-like tyrosine kinase 3 (FLT3)/VEGFR2/KDR/Flk-1/Histone deacetylase (HDAC) represents a novel and promising therapeutic strategy for acute myeloid leukemia. In this work, we hybridized essential pharmacophores from sorafenib and SAHA (vorinostat) and then conducted structure-activity relationship studies to identify two lead compounds 26 and 32 that potently inhibit FLT3, VEGFR2/KDR/Flk-1, and HDAC in a nanomolar range. In cell evaluation, compounds 26 and 32 exhibited potent proliferative activities against a panel of leukemia cells including MV4-11 and MOLM-13. Western blotting analysis also showed that compounds 26 and 32 suppressed the phosphorylation of FLT3, STAT3, and ERK1/2 and increased histone H3 acetylation in a dose-dependent manner, indicating the effective inhibition of FLT3, VEGFR2/KDR/Flk-1, and HDAC. Supported by its pharmacokinetic properties, compound 26 showed remarkable Anticancer efficacy in a MV4-11 xenograft model. Additionally, it demonstrated superior efficacy compared to midostaurin and gilteritinib in the Ba/F3-FLT3-ITD-N701K xenograft model.

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