Discovery of a 2,6-diarylpyridine-based hydroxamic acid derivative as novel histone deacetylase 8 and tubulin dual inhibitor for the treatment of neuroblastoma.
Discovery of a 2,6-diarylpyridine-based hydroxamic acid derivative as novel histone deacetylase 8 and tubulin dual inhibitor for the treatment of neuroblastoma.
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DOI：
10.1016/j.bioorg.2022.106112
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发表时间：
2022-08
影响因子：
5.1
通讯作者：
Hairong Tang;Yuru Liang;Hanchen Shen;S. Cai;Min Yu;Hongrui Fan;K. Ding;Yang Wang
中科院分区：
文献类型：
--
作者：
Hairong Tang;Yuru Liang;Hanchen Shen;S. Cai;Min Yu;Hongrui Fan;K. Ding;Yang Wang
本文通过在2，6-二芳基吡啶和2′-芳基查耳酮骨架上引入HDAC抑制剂的关键药效基团，合成了两个系列的HDAC/微管蛋白双重抑制剂。其中，基于2，6-二芳基吡啶的异羟肟酸10a对HDAC 8表现出良好的抑制活性（IC 50 = 117 nM），相对于HDAC 1和HDAC 6，其选择性分别为50倍和42倍。同时，10a能有效阻断微管蛋白的聚合，对BE-（2）-C细胞具有较强的抗增殖活性，IC 50值为17 nM。机制研究表明，10能阻滞细胞周期，诱导细胞凋亡，抑制集落形成。10a具有良好的理化性质和代谢稳定性。重要的是，10a在人神经母细胞瘤异种移植小鼠模型中表现出比临床HDAC抑制剂和微管蛋白抑制剂更好的抗肿瘤作用，无论是单独使用还是联合使用。这些结果突出了HDAC 8/微管蛋白双通道蛋白10a作为一种出色的抗肿瘤剂的优点。
Herein, two series of HDAC/tubulin dual inhibitors via introducing the key pharmacophore of HDAC inhibitor into the skeletons of 2,6-diarylpyridine and 2′-arylchalcone were synthesized. Among them, 2,6-diarylpyridine-based hydroxamic acid10aexhibited good inhibitory activity against HDAC8 (IC50= 117 nM) with 50-fold and 42-fold high selectivity relative to HDAC1 and HDAC6, respectively. Meanwhile,10adisrupted tubulin polymerization effectively and exhibited potent antiproliferative activity against BE-(2)-C cell line, with IC50value of 17 nM. Mechanism studies revealed that10ablocked cell cycle, induced cellular apoptosis and suppressed colony formation. Moreover,10apossessed good physicochemical properties and metabolic stability. Importantly,10aexhibited better antitumor effects in human neuroblastoma xenograft mice model than those of clinical HDAC inhibitor and tubulin inhibitor, whether used alone or in combination. These results highlighted the advantages of the HDAC8/tubulin dual inhibitor10aas an outstanding antitumor agent.