Design, Synthesis, and Evaluation of Benzimidazole-Based HDAC Inhibitors: Synergistic Effect with FLT3 Inhibitor against AML via Modulation of Tumor Metabolism

  • J Med Chem. 2026 Jul 9;69(13):15872-15887. doi: 10.1021/acs.jmedchem.6c01013.
Meng Liu  1  2 ,  Junxin Xue  3 ,  Changning Xue  4 ,  Huibin Qi  4 ,  Yuanzhi Tan  4 ,  Xiaohan Wang  3 ,  Shan Gao  4
Affiliations
  • 1. Department 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.
  • 2. College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China.
  • 3. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 4. Phase I Clinical Trail Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
PMID: 42312737 DOI: 10.1021/acs.jmedchem.6c01013
Abstract

Metabolic alterations, including aerobic glycolysis and Oxidative Phosphorylation (OXPHOS), drive the progression of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia (AML) and have emerged as attractive therapeutic targets. Histone deacetylases (HDACs) play a key role in these metabolic processes by regulating acetylation modifications of histones and nonhistone proteins. Herein, a series of novel benzimidazole derivatives were designed and synthesized based on the target structure. Among them, compound 6k exhibited potent inhibitory activity and selectivity for class I HDACs. Notably, the combination of 6k and the FLT3 Inhibitor quizartinib showed significant synergistic antiproliferative effects both in vitro and in vivo. Mechanistic studies showed that this combined strategy could simultaneously inhibit glycolysis and OXPHOS by blocking the PI3K/Akt signaling pathway, ultimately exerting antitumor activity. In summary, this study highlights 6k as a potential metabolic regulator and provides a promising therapeutic strategy for AML.

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