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.

Abstract

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.

• Authors: Hyo Jeong Yun, Garam Kim, Prem Khanal, Karam Kim, Chang-Hyun Oh, Hoo-Kyun Choi, Honglae Sohn, Hong Seok Choi
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 36 Issue 9 Pg. 1466-73 ( 2013) ISSN: 1347-5215 [Electronic] Japan
• PMID: 23748899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• N-(3-(4-benzamido-1H-pyrrolo(3,2-c)pyridin-1-yl)phenyl)-4-morpholino-3-(trifluoromethyl)benzamide
• Protein Kinase Inhibitors
• Transcription Factor AP-1
• Insulin-Like Growth Factor I
• Proto-Oncogene Proteins c-raf

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Benzamides (pharmacology)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cell Transformation, Neoplastic (chemically induced, drug effects, metabolism)
• Chickens
• Chorioallantoic Membrane
• Insulin-Like Growth Factor I
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, metabolism)
• Transcription Factor AP-1 (metabolism)