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
Department of Dermatology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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.
Exp Dermatol. 2015 Jul;24(7):503-9. doi: 10.1111/exd.12698. Epub 2015 Apr 27.
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.
血管内皮生长因子受体-2（VEGFR-2）和Janus激酶（JAK）/信号转导及转录激活因子3（STAT3）信号通路对肿瘤血管生成和转移至关重要。在本研究中，我们鉴定出（3-（2-（3-（吗啉甲基）苯基）噻吩并[3,2-b]吡啶-7-基氨基）苯酚（LCB03-0110）为一种有效的血管生成抑制剂。LCB03-0110在原代培养的人内皮细胞和癌细胞中抑制VEGFR-2和JAK/STAT3信号通路。体外激酶测定和分子模拟显示，LCB03-0110通过优先结合其激酶的ATP结合位点来抑制VEGFR-2、c-SRC和TIE-2激酶活性。LCB03-0110成功占据了VEGFR-2、c-SRC和TIE-2的疏水口袋。LCB03-0110还抑制缺氧诱导的HIF/STAT3以及表皮生长因子或血管生成素诱导的信号级联反应。此外，LCB03-0110抑制VEGF诱导的增殖、活力、迁移和毛细血管样管形成。LCB03-0110还抑制大鼠主动脉中内皮细胞的芽生以及小鼠基质胶栓试验中新生血管形成，同时也抑制小鼠的肺转移和肿瘤异种移植。我们的结果表明，LCB03-0110是一种潜在的小分子候选物，可阻断由VEGFR-2和JAK/STAT3信号异常激活介导的血管生成。
