Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 Signalling

Byung Hak Kim, Yoonji Lee, Hyun Yoo, Minghua Cui, Sungwoon Lee, Sun Young Kim, Jong Un Cho, Hyangsook Lee, Beom Seok Yang, Young Guen Kwon, Sun Choi, Tae Yoon Kim

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)503-509
Number of pages7
JournalExperimental Dermatology
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2015
Externally publishedYes

Fingerprint

Thienopyridines
Janus Kinases
STAT3 Transcription Factor
Vascular Endothelial Growth Factor Receptor-2
Phosphotransferases
Endothelial cells
Tumors
Assays
Endothelial Cells
Angiopoietins
Neoplasm Metastasis
Neoplasms
Angiogenesis Inhibitors
Molecular modeling
Blood vessels
Epidermal Growth Factor
Heterografts
Vascular Endothelial Growth Factor A
Blood Vessels
Aorta

Keywords

  • Angiogenesis
  • JAK/STAT3
  • LCB03-0110
  • VEGFR-2

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology

Cite this

Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 Signalling. / 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.

In: Experimental Dermatology, Vol. 24, No. 7, 01.07.2015, p. 503-509.

Research output: Contribution to journalArticle

Kim, BH, Lee, Y, Yoo, H, Cui, M, Lee, S, Kim, SY, Cho, JU, Lee, H, Yang, BS, Kwon, YG, Choi, S & Kim, TY 2015, 'Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 Signalling', Experimental Dermatology, vol. 24, no. 7, pp. 503-509. https://doi.org/10.1111/exd.12698
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. / Anti-angiogenic activity of thienopyridine derivative LCB03-0110 by targeting VEGFR-2 and JAK/STAT3 Signalling. In: Experimental Dermatology. 2015 ; Vol. 24, No. 7. pp. 503-509.
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AU - Lee, Yoonji

AU - Yoo, Hyun

AU - Cui, Minghua

AU - Lee, Sungwoon

AU - Kim, Sun Young

AU - Cho, Jong Un

AU - Lee, Hyangsook

AU - Yang, Beom Seok

AU - Kwon, Young Guen

AU - Choi, Sun

AU - Kim, Tae Yoon

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AB - 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.

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