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发现新型基于咪唑并噻唑的异羟肟酸衍生物作为强效吲哚胺2,3-双加氧酶1和组蛋白去乙酰化酶6双重抑制剂

Discovery of Novel Imidazothiazole-Based Hydroxamic Acid Derivatives as Potent Indoleamine 2,3-Dioxygenase 1 and Histone Deacetylase 6 Dual Inhibitors.

作者信息

Zhang Shi, Wang Yan-Fei, Lu Hai-Rui, Yang Xue-Qin, Zhang Ye, Ma Xian-Li, Huang Ri-Zhen

机构信息

Guangxi Key Laboratory of Drug Discovery and Optimization, School of Pharmacy, Guilin Medical University, Guilin 541199, China.

Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China.

出版信息

Molecules. 2025 Jun 7;30(12):2508. doi: 10.3390/molecules30122508.

DOI:10.3390/molecules30122508
PMID:40572474
Abstract

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound () showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound interacted with IDO1 and HDAC6. Moreover, compound was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents.

摘要

为了同时利用免疫治疗和表观遗传抗肿瘤药物，基于药效团融合策略设计了一系列基于咪唑并噻唑的异羟肟酸衍生物，并将其评估为有效的吲哚胺2,3-双加氧酶1（IDO1）和组蛋白去乙酰化酶6（HDAC6）双重抑制剂。在这些抑制剂中，最有效的化合物（）表现出相当可观的IDO1抑制活性，并且对HDAC6相对于其他HDAC亚型具有良好的选择性。通过蛋白质印迹分析验证了（）对HDAC6的细胞内抑制作用。对接研究表明化合物（）与IDO1和HDAC6相互作用的可能结合模式。此外，发现化合物（）在HCT-116细胞中将细胞周期阻滞在G2/M期。特别地，化合物（）在携带CT26肿瘤的BALB/c小鼠模型中也表现出有效的体内抗肿瘤功效，且无明显毒性。总的来说，这项工作提供了一种有前景的先导化合物，可作为IDO1/HDAC6双重抑制剂用于开发新型抗肿瘤药物。

相似文献

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Discovery of Novel Imidazothiazole-Based Hydroxamic Acid Derivatives as Potent Indoleamine 2,3-Dioxygenase 1 and Histone Deacetylase 6 Dual Inhibitors.

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本文引用的文献

[1]
Discovery of novel 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives as potent carbonic anhydrase IX inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer.

Bioorg Chem. 2024-9

[2]
Discovery of novel itaconimide-based derivatives as potent HDAC inhibitors for the efficient treatment of prostate cancer.

Eur J Med Chem. 2024-4-5

[3]
Discovery of 4-(N-dithiobenzyl piperazine)-1,8-naphthalimide as a potent multi-target antitumor agent with good efficacy, limited toxicity, and low resistance.

Eur J Med Chem. 2024-1-5

[4]
Hydroxamic acid hybrids: Histone deacetylase inhibitors with anticancer therapeutic potency.

Eur J Med Chem. 2023-12-15

[5]
Technologies of targeting histone deacetylase in drug discovery: Current progress and emerging prospects.

Eur J Med Chem. 2023-12-5

[6]
Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity.

Eur J Med Chem. 2023-11-15

[7]
Targeting histone deacetylases for cancer therapy: Trends and challenges.

Acta Pharm Sin B. 2023-6

[8]
Discovery of novel sulfonamide chromone-oxime derivatives as potent indoleamine 2,3-dioxygenase 1 inhibitors.

Eur J Med Chem. 2023-6-5

[9]
Discovery of two biotin-PEG4‑diarylidenyl piperidone prodrugs as potent antitumor agents with good efficacy, limited toxicity, and low resistance.

Bioorg Chem. 2023-2

[10]
Combination cancer immunotherapies: Emerging treatment strategies adapted to the tumor microenvironment.

Sci Transl Med. 2022-11-9

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