Anti‐angiogenic activity of thienopyridine derivative LCB 03‐0110 by targeting VEGFR ‐2 and JAK / STAT 3 Signalling

• Published in: Experimental dermatology Vol. 24; no. 7; pp. 503 - 509
• Main Authors: Kim, Byung‐Hak, Lee, Yoonji, Yoo, Hyun, Cui, Minghua, Lee, Sungwoon, Kim, Sun Young, Cho, Jong Un, Lee, Hyangsook, Yang, Beom‐Seok, Kwon, Young‐Guen, Choi, Sun, Kim, Tae‐Yoon
• Format: Journal Article
• Language: English
• Published: 01.07.2015
• ISSN: 0906-6705; 1600-0625
• DOI: 10.1111/exd.12698

Abstract Vascular endothelial growth factor receptor‐2 ( VEGFR ‐2) and Janus kinase ( JAK )/signal transducer and activator of transcription 3 ( STAT 3) 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 ( LCB 03‐0110) as a potent angiogenesis inhibitor. LCB 03‐0110 inhibited VEGFR ‐2 and JAK / STAT 3 signalling in primary cultured human endothelial cells and cancer cells. An in vitro kinase assay and molecular modelling revealed that LCB 03‐0110 inhibited VEGFR ‐2, c‐ SRC and TIE ‐2 kinase activity via preferential binding at the ATP ‐binding site of their kinases. LCB 03‐0110 successfully occupied the hydrophobic pocket of VEGFR ‐2, c‐ SRC and TIE ‐2. LCB 03‐0110 also inhibited hypoxia‐induced HIF / STAT 3 and EGF ‐ or angiopoietin‐induced signalling cascades. In addition, LCB 03‐0110 inhibited VEGF ‐induced proliferation, viability, migration and capillary‐like tube formation. LCB 03‐0110 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 LCB 03‐0110 is a potential candidate small molecule for blocking angiogenesis mediated by aberrant activation of VEGFR ‐2 and JAK / STAT 3 signalling.