title: Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 Signalling.
abstract: Vascular endothelial growth factor receptor-2 (VEGFR-2) and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signalling are important for tumor angiogenesis and metastasis. In this study, we identified (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol (LCB03-0110) as a potent angiogenesis inhibitor. LCB03-0110 inhibited VEGFR-2 and JAK/STAT3 signalling in primary cultured human endothelial cells and cancer cells. An in vitro kinase assay and molecular modelling revealed that LCB03-0110 inhibited VEGFR-2, c-SRC and TIE-2 kinase activity via preferential binding at the ATP-binding site of their kinases. LCB03-0110 successfully occupied the hydrophobic pocket of VEGFR-2, c-SRC and TIE-2. LCB03-0110 also inhibited hypoxia-induced HIF/STAT3 and EGF- or angiopoietin-induced signalling cascades. In addition, LCB03-0110 inhibited VEGF-induced proliferation, viability, migration and capillary-like tube formation. LCB03-0110 also suppressed the sprouting of endothelial cells in the rat aorta and the formation of new blood vessels in the mouse Matrigel plug assay, but also suppressed pulmonary metastasis and tumor xenograft in mice. Our results suggest that LCB03-0110 is a potential candidate small molecule for blocking angiogenesis mediated by aberrant activation of VEGFR-2 and JAK/STAT3 signalling.
authors: Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors: Byung-Hak
authors: BH
authors: Kim
authors: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul, Korea.
authors: Yoonji
authors: Y
authors: Lee
authors: Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors: Hyun
authors: H
authors: Yoo
authors: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul, Korea.
authors: Minghua
authors: M
authors: Cui
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors: Sungwoon
authors: S
authors: Lee
authors: LegoChem Biosciences, Inc., Daejeon, Korea.
authors: Sun Young
authors: SY
authors: Kim
authors: LegoChem Biosciences, Inc., Daejeon, Korea.
authors: Jong Un
authors: JU
authors: Cho
authors: LegoChem Biosciences, Inc., Daejeon, Korea.
authors: Hyangsook
authors: H
authors: Lee
authors: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Korea.
authors: Beom-Seok
authors: BS
authors: Yang
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors: Young-Guen
authors: YG
authors: Kwon
authors: National Leading Research Laboratory (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Graduate School of Pharmaceutical Sciences, and Global Top 5 Research Program, Ewha Womans University, Seoul, Korea.
authors: Sun
authors: S
authors: Choi
authors: Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors: Tae-Yoon
authors: TY
authors: Kim
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000631:Aminopyridines / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D051381:Rats; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C571281:3-(2-(3-(morpholinomethyl)phenyl)thieno(3,2-b)pyridin-7-ylamino)phenol; D000631:Aminopyridines; D020533:Angiogenesis Inhibitors; D050796:STAT3 Transcription Factor; D013876:Thiophenes; D000255:Adenosine Triphosphate; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2; D000081247:CSK Tyrosine-Protein Kinase; D053612:Janus Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: JAK/STAT3; LCB03-0110; VEGFR-2; angiogenesis