Related Experiment Video
Updated: Jul 17, 2025
Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
Published on: June 6, 2025
Rational discovery of dual FLT3/HDAC inhibitors as a potential AML therapy
Zhijie Wang1, Donglin Wu2, Xiaofei Zhao2
1ShenZhen Hospital, Southern Medical University, Shenzhen, 518000, PR China; School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
Abstract:
Acute myeloid leukemia (AML) patients often experience poor therapeutic outcomes and relapse after treatment with single-target drugs, representing the urgent need of new therapies. Simultaneous inhibition of multiple oncogenic signals is a promising strategy for tumor therapy. Previous studies have reported that concomitant inhibition of Fms-like tyrosine kinase 3 (FLT3) and histone deacetylases (HDACs) can significantly improve the therapeutic efficacy for AML. Herein, a series of novel dual FLT3/HDAC inhibitors were developed through a rational structure-based drug design strategy for the first time. Among them, multiple compounds showed potent and equivalent inhibitory activities against FLT3-ITD and HDAC1, with the representative compound 63 selectively inhibiting HDAC class I (HDAC1/2/3/8) and IIB isoforms (HDAC6) related to tumorigenesis, and intensively blocking proliferation of MV4-11 cells. The antiproliferation activity was proven to depend on the dual inhibition of FLT3 and HDAC1. Mechanism assays demonstrated that 63 prohibited both FLT3 and HDAC pathways, induced apoptosis and arrested cell cycle in MV4-11 cells in a dose-dependent manner. In summary, this study validated the therapeutic potential of a kind of dual FLT3/HDAC inhibitors for AML and provided novel compounds for further biological investigation on concomitant inhibition of FLT3/HDAC pathways. Additionally, the structure-based drug design strategy described herein may provide profound enlightenment for developing superior anti-AML drugs.
Insights
Novel dual inhibitors targeting Fms-like tyrosine kinase 3 (FLT3) and histone deacetylases (HDACs) show promise for treating acute myeloid leukemia (AML). These compounds effectively inhibit cancer cell proliferation by blocking both FLT3 and HDAC pathways.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) patients often face poor outcomes and relapse due to single-target drug limitations.
- Simultaneous inhibition of multiple oncogenic signals presents a promising therapeutic strategy for AML.
- Previous research suggests combining Fms-like tyrosine kinase 3 (FLT3) and histone deacetylase (HDAC) inhibition enhances AML treatment efficacy.
Purpose of the Study:
- To develop novel dual inhibitors targeting both FLT3 and HDAC pathways for AML treatment.
- To evaluate the inhibitory activity and antiproliferative effects of these novel compounds.
- To elucidate the mechanism of action for the most potent dual inhibitor.
Main Methods:
- Rational structure-based drug design was employed to create novel dual FLT3/HDAC inhibitors.
- In vitro assays were used to assess inhibitory activities against FLT3-ITD and HDAC isoforms.
- Cell proliferation, apoptosis, and cell cycle arrest were analyzed in MV4-11 AML cells.
Main Results:
- Several novel compounds demonstrated potent and equivalent inhibition of FLT3-ITD and HDAC1.
- Compound 63 selectively inhibited tumorigenesis-related HDAC class I and IIB isoforms.
- Compound 63 effectively blocked MV4-11 cell proliferation, induced apoptosis, and arrested cell cycle in a dose-dependent manner, confirming dual FLT3/HDAC pathway inhibition.
Conclusions:
- The study successfully developed novel dual FLT3/HDAC inhibitors with therapeutic potential for AML.
- Compound 63 represents a promising candidate for further investigation in AML treatment.
- The structure-based drug design strategy offers a valuable approach for developing advanced anti-AML therapies.
