title: 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.affiliation: College of Pharmacy, Chosun University.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Yun
authors.forename: Garam
authors.initials: G
authors.lastname: Kim
authors.forename: Prem
authors.initials: P
authors.lastname: Khanal
authors.forename: Karam
authors.initials: K
authors.lastname: Kim
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Oh
authors.forename: Hoo-Kyun
authors.initials: HK
authors.lastname: Choi
authors.forename: Honglae
authors.initials: H
authors.lastname: Sohn
authors.forename: Hong Seok
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000378:metabolism; D002645:Chickens; D049033:Chorioallantoic Membrane; D007334:Insulin-Like Growth Factor I; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C587448:N-(3-(4-benzamido-1H-pyrrolo(3,2-c)pyridin-1-yl)phenyl)-4-morpholino-3-(trifluoromethyl)benzamide; D047428:Protein Kinase Inhibitors; D018808:Transcription Factor AP-1; D007334:Insulin-Like Growth Factor I; D019908:Proto-Oncogene Proteins c-raf