Kehui Zhang, Fangfang Lai, Songwen Lin, Ming Ji, Jingbo Zhang, Yan Zhang, Jing Jin, Rong Fu, Deyu Wu, Hua Tian, Nina Xue, Li Sheng, Xiaowen Zou, Yan Li, Xiaoguang Chen, Heng Xu.Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia Activity. Inks, Nathan Dolloff, Stephanie Halene, Sherine S. Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy. Nilanjan Adhikari, Tarun Jha, Balaram Ghosh.Potent Hydrazide-Based HDAC Inhibitors with a Superior Pharmacokinetic Profile for Efficient Treatment of Acute Myeloid Leukemia In Vivo. Yuqi Jiang, Jie Xu, Kairui Yue, Chao Huang, Mengting Qin, Dongyu Chi, Qixin Yu, Yue Zhu, Xiaohan Hou, Tongqiang Xu, Min Li, C.Determination of Slow-Binding HDAC Inhibitor Potency and Subclass Selectivity. This article is cited by 40 publications.
In vitro and ex vivo characterization of our lead analogues’ efficacy, selectivity, and toxicity profiles demonstrate that they possess low nanomolar activity against models of acute myeloid leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition.
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With the goal of developing a second generation of HDAC inhibitors lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations.
One of the biggest hurdles yet to be overcome for the continued improvement of histone deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid.