게시판

Principal Investigator
- Misun Won, Ph.D, Biomedical Genomics Research Center / August 2013

R&D Background
- HIF-1α has been recognized as a crucial molecular target for cancer therapy, and various HIF-1α inhibitors derived from natural products or a chemical library have been developed. We have reported the synthesis and biological evaluation of LW6, which is now commercially available as a HIF-1α inhibitor. Since the regulation of HIF-1α expression is very complex, the understanding LW6 the exact mechanism is not easy without identification of the direct binding molecule.

Research Summary
- A series of LW6-derived chemical probes were designed and synthesized by installing a clickable tag and a photoactivatable moiety. Using an clickable probe with flourescent tag, we found that LW6 localized in the mitochondria. In addition, Malate dehydrogenase 2 (MDH2) of TCA cycle was identified as a target protein of LW6 by 2-D PAGE with double photolabeling of both LW6 and a negative control. In parallel with the MDH2 inhibition, LW6 and MDH2 inhibitor L-thyroxine suppressed hypoxia-induced HIF-1a accumulation by inhibiting mitochondrial respiration. In conclusion, LW6 binds to MDH2 blocking mitochondrial respiration, resulting in increased local oxygen tension for degradation of HIF-1α.
Applied Cases and Effects
- A high level of MDH2 expression was associated with shorter, relapse-free survival and chemoresistance of prostate cancer patients. The study of the HIF-1α inhibitor LW6 concerning inhibition of MDH2 activity will provide information on the relevance of MDH2 to cancer and its clinical benefit. A high level of MDH2 expression was associated with shorter, relapse-free survival and chemoresistance of prostate cancer patients. The study of the HIF-1α inhibitor LW6 concerning inhibition of MDH2 activity will provide information on the relevance of MDH2 to cancer and its clinical benefit.




Principal Investigator Misun Won, Ph.D, Biomedical Genomics Research Center / August 2013 R&D Background HIF-1α has been recognized as a crucial molecular target for cancer therapy, and various HIF-1α inhibitors derived from natural products or a chemical library have been developed. We have reported the synthesis and biological evaluation of LW6, which is now commercially available as a HIF-1α inhibitor. Since the regulation of HIF-1α expression is very complex, the understanding LW6 the exact mechanism is not easy without identification of the direct binding molecule. Research Summary A series of LW6-derived chemical probes were designed and synthesized by installing a clickable tag and a photoactivatable moiety. Using an clickable probe with flourescent tag, we found that LW6 localized in the mitochondria. In addition, Malate dehydrogenase 2 (MDH2) of TCA cycle was identified as a target protein of LW6 by 2-D PAGE with double photolabeling of both LW6 and a negative control. In parallel with the MDH2 inhibition, LW6 and MDH2 inhibitor L-thyroxine suppressed hypoxia-induced HIF-1a accumulation by inhibiting mitochondrial respiration. In conclusion, LW6 binds to MDH2 blocking mitochondrial respiration, resulting in increased local oxygen tension for degradation of HIF-1α. Applied Cases and Effects A high level of MDH2 expression was associated with shorter, relapse-free survival and chemoresistance of prostate cancer patients. The study of the HIF-1α inhibitor LW6 concerning inhibition of MDH2 activity will provide information on the relevance of MDH2 to cancer and its clinical benefit. A high level of MDH2 expression was associated with shorter, relapse-free survival and chemoresistance of prostate cancer patients. The study of the HIF-1α inhibitor LW6 concerning inhibition of MDH2 activity will provide information on the relevance of MDH2 to cancer and its clinical benefit.