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

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.