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

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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
Author(s)
D Song; C Lee; Y J Kook; Soo Jin Oh; Jong Soon Kang; H J Kim; G Han
Bibliographic Citation
European Journal of Medicinal Chemistry, vol. 126, pp. 997-1010
Publication Year
2017
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
Keyword
Epigenetic controlHDAC inhibitionProtein stabilizationRUNX3RUNX3 acetylation
ISSN
0223-5234
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.ejmech.2016.11.055
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of National Bio-Infrastructure > Laboratory Animal Resource & Research Center > 1. Journal Articles
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