2. Academic Validation
  3. HDAC11 Inhibition as a Potential Therapeutic Strategy for AML: Target Identification, Lead Discovery, Antitumor Potency, and Mechanism Investigation

HDAC11 Inhibition as a Potential Therapeutic Strategy for AML: Target Identification, Lead Discovery, Antitumor Potency, and Mechanism Investigation

  • J Med Chem. 2025 Apr 24;68(8):8124-8142. doi: 10.1021/acs.jmedchem.4c02550.
Maoshuo Yang 1 2,  Wei Zhao 1,  Jinwei Zhang 1,  Lanlan Liu 1 2,  Sijia Tian 1,  Yaqing Miao 1,  Yongxin Jia 1,  Limei Wang 2,  Qipeng Chai 1,  Qiang Wang 3,  Fabao Liu 2,  Yingjie Zhang 1,  Xiaona You 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 2 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.
  • 3 School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan, Hubei 430074, P.R. China.
PMID: 40177883 DOI: 10.1021/acs.jmedchem.4c02550
Abstract

Herein, we identified that HDAC11 is involved in the pathogenesis of AML and is a potential therapeutic target for AML. Considering the scarcity of HDAC11 inhibitors, structurally novel HDAC11 inhibitors were developed, identifying A9 as the most potent one, which phenocopied the Apoptosis induction, cell cycle arrest, and differentiation promotion effects of HDAC11 knockdown in AML cells. Moreover, A9 not only promoted iron uptake by upregulating TF and TFRC but also promoted iron release by upregulating HMOX1, which cooperatively led to iron homeostasis disruption and the consequent Ferroptosis in AML cells. Mechanism investigation indicated that A9-induced HMOX1 upregulation was due to the activation of the p62-Keap1-Nrf2 pathway. Notably, the combination of A9 with chemotherapy drugs synergistically reduced AML cell viability in vitro. The robust in vivo anti-AML efficacy of A9, alone and combined with cytarabine, was also validated. Collectively, our study revealed pharmacological inhibition of HDAC11 as a potential therapeutic strategy for AML.

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