Author: Liu, Fabao ; Zhang, Jinwei ; Zhang, Yingjie ; Miao, Yaqing ; Tian, Sijia ; Liu, Lanlan ; Chai, Qipeng ; You, Xiaona ; Zhao, Wei ; Yang, Maoshuo ; Wang, Limei ; Jia, Yongxin ; Wang, Qiang

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.

01 Oct 2024·European Journal of Medicinal Chemistry

Biological function and small molecule inhibitors of histone deacetylase 11

Review

Author: Li, Xiaoyang ; Hou, Xinlu ; Jia, Geng ; Liu, Jinyu ; Jiang, Yuqi

HDAC11, as a rising star in the histone deacetylase (HDAC) family, has attracted widespread interest in the biomedical field in recent years specially owing to its high defatty-acylase activity compared its innate deacetylase activity. Numerous studies have provided evidence indicating the crucial involvement of HDAC11 in cancers, immune responses, and metabolic processes. Several potent and selective HDAC11 inhibitors have been discovered and identified, which is crucial for exploring the function of HDAC11 and its potential therapeutic applications. Herein, we present a critical overview of the current advances in the biological function of HDAC11 and its inhibitors. We initially discuss the physiological functions of HDAC11 and its pathological roles in relevant diseases. Subsequently, our main focus centers on the design strategy and development process of HDAC11 inhibitors. Additionally, we address significant challenges and outline future directions in this field. This perspective may provide guidance for the further development of HDAC11 inhibitors and their prospects in disease treatment.

01 Oct 2024·Archiv der Pharmazie

Utilization of an optimized AlphaFold protein model for structure‐based design of a selective HDAC11 inhibitor with anti‐neuroblastoma activity

Article

Author: Sippl, Wolfgang ; Schutkowski, Mike ; Robaa, Dina ; Baselious, Fady ; Tripathee, Sunita ; Hilscher, Sebastian ; Barinka, Cyril ; Hagemann, Sven ; Hüttelmaier, Stefan

AbstractAlphaFold is an artificial intelligence approach for predicting the three‐dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 µM on neuroblastoma cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	China	Shandong University	03 Apr 2025

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