Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity

A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[<i>d</i>][1, <i>3</i>]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5-<i>a</i>]pyridin-2-yl)amino)methyl)-<i>N</i>-hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC<sub>50</sub> values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.

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Publication Details

Journal
Journal of Enzyme Inhibition and Medicinal Chemistry
Published
2024-10-08
DOI
https://doi.org/10.1080/14756366.2024.2409771
Citations
8
Primary Topic
Histone Deacetylase Inhibitors Research
Type
article
Field-Weighted Citation Impact
1.87

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article

Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity

Shiyuan Liu, Jing Shi, Zhengshui Xu, Ranran Kong et al.
8 citations
Journal of Enzyme Inhibition and Medicinal Chemistry
Histone Deacetylase Inhibitors Research
1.87
article

Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity

Shiyuan Liu, Jing Shi, Zhengshui Xu, Ranran Kong, Xin Chen, Xingjie Wang, Changchun Ye, Zilu Chen
article en
8 citations

Abstract

A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[<i>d</i>][1, <i>3</i>]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5-<i>a</i>]pyridin-2-yl)amino)methyl)-<i>N</i>-hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC<sub>50</sub> values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.

Journal of Enzyme Inhibition and Medicinal ChemistryVol. 39(1)
Rutgers, The State University of New Jersey (US), First Affiliated Hospital of Xi'an Jiaotong University (CN), Second Affiliated Hospital of Xi'an Jiaotong University (CN), Rutgers Cancer Institute (US), Xi'an Jiaotong University (CN), Northwest A&F University (CN)
National Natural Science Foundation of China, Key Research and Development Projects of Shaanxi Province, Natural Science Basic Research Program of Shaanxi Province
Zero hunger
Openalex Percentile: Top 14%
Histone Deacetylase Inhibitors Research
1.87
DOIOpen Access PDFOpenAlex
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