2. Academic Validation
  3. Discovery of a Hydroxamic Acid-Based HDAC11 Isoform-Selective Inhibitor with Oral Anti-AML Potency

Discovery of a Hydroxamic Acid-Based HDAC11 Isoform-Selective Inhibitor with Oral Anti-AML Potency

  • J Med Chem. 2026 Mar 26;69(6):6816-6834. doi: 10.1021/acs.jmedchem.5c03107.
Qipeng Chai 1,  Maoshuo Yang 2,  Chunxi Liu 3,  Xiaolan Zhu 4,  Lina Liu 4,  Wei Zhao 1,  Xintong Xue 1,  Jinwei Zhang 1,  Lanlan Liu 2 4,  Wenjing Wang 4,  Fabao Liu 2,  Xiaona You 4,  Yingjie Zhang 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, P. R. China.
  • 2 Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, P. R. China.
  • 3 Department of Pharmacy, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, P. R. China.
  • 4 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 250012, P. R. China.
PMID: 41787751 DOI: 10.1021/acs.jmedchem.5c03107
Abstract

Our previous study not only demonstrated that HDAC11 is a potential therapeutic target for AML but also discovered a specific HDAC11 Inhibitor A9 as an anti-AML lead compound. The purpose of the present study was to discover novel specific HDAC11 inhibitors with improved drug-like properties through structural modification and optimization of A9. Among the newly synthesized A9 derivatives, compound 25 stood out as a potent and specific HDAC11 Inhibitor with desirable liver microsomal stability. Notably, compared with the well-known HDAC11 Inhibitor FT895, compound 25 exhibited much stronger multiple anti-AML effects including proliferation inhibition, Apoptosis induction, cell cycle arrest, differentiation promotion, and Ferroptosis induction. Moreover, combination of 25 and ivosidenib, an approved targeted therapeutic drug for AML, showed strong synergistic anti-AML potency. Satisfyingly, compound 25 exhibited acceptable oral pharmacokinetic parameters in mouse, which supported its robust oral anti-AML potency in an MLL-AF9-induced mouse AML model, both alone and in combination with ivosidenib.

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