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제118회 대한화학회 학술발표회, 총회 및 기기전시회 Structural Design and Biological Evaluation of Pyridone-Based Histone Deacetylase Inhibitors for Recovery of Activation and Stability of RUNX3 [세진시아이 포스터상]

2016년 8월 25일 14시 26분 14초
MEDI.P-485 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 13일 (목요일) 11:00~12:30
저자 및
국윤정, 한균희1,*
연세대학교 융합오믹스 의생명과학과, Korea
1연세대학교 생명공학과, Korea
Histone deacetylases (HDACs) have been great research targets for cancer treatment since their aberrant expression due to abnormal epigenetic change was known to play a significant role in tumor onset and progression. Recently, HDAC inhibitors are reported to stabilize a tumor suppressor called runt-related transcription factor 3 (RUNX3) and recover its anticancer activity that is commonly found repressed in various tumor cells. In the previous study, we introduced a new approach to cancer treatment using HDAC inhibitors that restores RUNX3 activity and also presented a series of novel compounds to recover RUNX3 activity. In this study, we reported a new series of HDAC inhibitors by introducing an alkenyl linker between the core and the cap group to improve biological activity and metabolic stability. Through structure-activity relationship (SAR) study, we found that the introduction of an alkenyl group enhanced rigidity of the compound structure, thus facilitating a better fit to the HDAC active site, and increased metabolic stability. We conducted in vitro biological assay to select compounds with high level of activity and metabolic stability. Then, we analyzed in vivo anti-cancer effect of the selected compounds in a xenograft regression model using gastric cancer cell lines. Compound 7k showed the highest inhibition level of tumor growth as a result, so it was selected for further pharmacokinetic evaluation. Showing a high oral bioavailability, compound 7k showed a prospect of being a candidate for anticancer chemotherapeutic agent with high efficacy and metabolic stability.