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  3. Rational discovery of dual FLT3/HDAC inhibitors as a potential AML therapy

Rational discovery of dual FLT3/HDAC inhibitors as a potential AML therapy

  • Eur J Med Chem. 2023 Nov 15;260:115759. doi: 10.1016/j.ejmech.2023.115759.
Zhijie Wang 1,  Donglin Wu 2,  Xiaofei Zhao 2,  Canlin Liu 2,  Siming Jia 2,  Qindi He 2,  Fei Huang 2,  Zitian Cheng 2,  Tao Lu 3,  Yadong Chen 4,  Yun Chen 5,  Pei Yang 6,  Shuai Lu 7
Affiliations

Affiliations

  • 1 ShenZhen Hospital, Southern Medical University, Shenzhen, 518000, PR China; School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 2 School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: lutao@cpu.edu.cn.
  • 4 Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: chenyadong@gmail.com.
  • 5 Edmond H. Fischer Translational Medical Research Laboratory, Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, PR China. Electronic address: cheny653@mail.sysu.edu.cn.
  • 6 Experimental Teaching Demonstration Center of Pharmaceutical Chemistry, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: pharmyp@163.com.
  • 7 School of Science, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: lu_shuai@cpu.edu.cn.
PMID: 37659198 DOI: 10.1016/j.ejmech.2023.115759
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.

Keywords

AML; Dual inhibitor; FLT3; HDAC.

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