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Title 

Improving potency and metabolic stability by introducing an alkenyl linker to pyridine-based histone deacetylase inhibitors for orally available RUNX3 modulators

Authors 

D SongC LeeY J KookSoo Jin OhJong Soon KangH J KimG Han

Publisher 

Elsevier

Issue Date 

2017

Citation 

European Journal of Medicinal Chemistry, vol. 126, no. 0, pp. 997-1010

Keywords 

Epigenetic controlHDAC inhibitionProtein stabilizationRUNX3RUNX3 acetylation

Abstract 

RUNX3, a tumor suppressor, is suppressed in various cancers by abnormal epigenetic changes. Histone deacetylases (HDACs) can deacetylate the lysine residues of RUNX3, followed by degradation via a ubiquitin-mediated pathway. Inhibition of HDAC leads to functional restoration of the RUNX3 protein by epigenetic expression and RUNX3 protein stabilization. We previously reported a series of HDAC inhibitors that restored RUNX3 function. In the present study, we introduced an alkenyl linker group to pyridine-based HDAC inhibitors to improve their potencies and chemical properties. This alkenyl linker made the compounds more rigid, facilitating a better fit than alkyl moieties to the active site of HDAC proteins. Most compounds in this series exhibited potent RUNX activities, HDAC inhibitory activities, and inhibitory activities towards the growth of human cancer cell lines. Notably, one of these derivatives, (E)-3-(1-cinnamyl-2-oxo-1,2-dihydropyridin-3-yl)-N-hydroxyacrylamide (7k), showed excellent properties in a microsomal stability study, in a xenograft study, and in an in vivo pharmacokinetic evaluation. Modulation of RUNX3 therefore results in highly potent and orally available anticancer chemotherapeutic agents

ISSN 

0223-5234

Link 

http://dx.doi.org/10.1016/j.ejmech.2016.11.055

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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