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Published on: October 17, 2025

Design, Synthesis, and Evaluation of Benzimidazole-Based HDAC Inhibitors: Synergistic Effect with FLT3 Inhibitor

Meng Liu1,2, Junxin Xue3, Changning Xue4

  • 1Department of Clinical Pharmacy, Shandong Pediatric Drug Clinical Evaluation and R&D Research Center of Engineering Technology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, China.

Journal of Medicinal Chemistry
|June 18, 2026
PubMed

Insights

A novel compound, 6k, targets metabolic pathways in acute myeloid leukemia (AML) with FLT3-ITD mutations. Combining 6k with quizartinib shows synergistic effects by inhibiting glycolysis and OXPHOS, offering a promising AML therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Metabolic reprogramming, including aerobic glycolysis and oxidative phosphorylation (OXPHOS), is crucial for FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia (AML) progression.
  • Histone deacetylases (HDACs) regulate cellular metabolism through histone and nonhistone protein acetylation, making them potential therapeutic targets in AML.

Purpose of the Study:

  • To design and synthesize novel benzimidazole derivatives targeting metabolic pathways in AML.
  • To evaluate the efficacy of a novel compound, 6k, and its combination with quizartinib in FLT3-ITD mutated AML.

Main Methods:

  • Synthesis of novel benzimidazole derivatives.
  • Assessment of inhibitory activity and selectivity for class I HDACs.
  • In vitro and in vivo evaluation of combined treatment with compound 6k and quizartinib.
  • Mechanistic studies involving the PI3K/AKT signaling pathway.

Main Results:

  • Compound 6k demonstrated potent inhibitory activity and selectivity for class I HDACs.
  • The combination of 6k and quizartinib exhibited significant synergistic antiproliferative effects in vitro and in vivo.
  • The combined strategy inhibited both glycolysis and OXPHOS by blocking the PI3K/AKT pathway.

Conclusions:

  • Compound 6k acts as a potential metabolic regulator in AML.
  • The combination of 6k and quizartinib presents a promising therapeutic strategy for AML by targeting key metabolic pathways and signaling.

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