MEK/ERK의 신호전달과정의 억제와 세포사멸과정의 활성을 통한 암세포 형질전환을 억제하는 새로운 sorafenib 유도체들의 발굴

Abstract

Sorafenib (Nexavar®) derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of its derivatives, we synthesized a new series of derivatives. In this study, we demonstrate that Gm6, Gm7 and KIST211905 inhibits neoplastic cell transformation through inhibition of MAPK signaling pathway and activation of apoptotic signaling in human melanoma cells. The Gm6, Gm7 and KIST211905 inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK) and extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase (ERK) signaling pathways in A375 cells. In addition, the Gm6, Gm7 and KIST211905 induced the cleavage of capase-3 as well as poly (ADP-ribose) polymerase (PARP), which were shown to be required for apoptosis to proceed in various cell lines, in A375 cells. Consistent with these observations, the Gm6, Gm7 and KIST211905 suppressed the colony formation of A375 cells in soft agar. Taken together, these results suggest that the Gm6, Gm7 and KIST211905 might exert chemotherapeutic effects through the inhibition of phosphorylation of MAPK and activation of apoptotic signaling pathway in melanoma.