Inhibitory effects of a new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, on activator protein-1 activity and neoplastic cell transformation induced by insulin-like growth factor-1.

Diarylureas and diarylamides derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of diarylurea and diarylamide derivatives, we synthesized a new series of diarylureas and diarylamides containing pyrrolo[3,2-c]pyridine scaffold. In this study, we demonstrate that a N-(3-(4-benzamido-1H-pyrrolo[3,2-c]pyridin-1-yl)phenyl)-4-morpholino-3-(trifluoromethyl)benzamide, KIST101029, inhibits neoplastic cell transformation induced by insulin-like growth factor 1 (IGF-1) in mouse epidermal JB6 Cl41 cells. The KIST101029 compound inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK), c-jun N-terminal kinases (JNK), and mechanistic target of rapamycin (mTOR) signaling pathways induced by IGF-1 in JB6 Cl41 cells, resulting in the inhibition of c-fos and c-jun transcriptional activity. In addition, the KIST101029 inhibited the associated activator protein-1 (AP-1) transactivation activity and cell transformation induced by IGF-1 in JB6 Cl41 cells. Consistent with these observations, in vivo chorioallantoic membrane assay also showed that the KIST101029 inhibited IGF-1-induced tumorigenicity of JB6 Cl41 cells. Importantly, KIST101029 suppressed the colony formation of A375 cells in soft agar. Taken together, these results indicate that a KIST101029 might exert chemopreventive effects through the inhibition of phosphorylation of MAPK and mTOR signaling pathway.