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.
Bibliographical noteFunding Information:
This research was supported by a grant from the Translational Research Center for Protein Function Control (TRCP 2016R1A5A1004694), the Ministry of Science, ICT and Future Planning (Grant NRF-2013M3A6A4072536), the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (Grant NRF-2015R1A6A3A01020077), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1324), the Yonsei University Research Fund (Post Doc. Researcher Supporting Program 2015-12-0005), and the KRIBB Research Initiative Program.
© 2016 Elsevier Masson SAS
All Science Journal Classification (ASJC) codes
- Drug Discovery
- Organic Chemistry