Targeting VEGFR-2 and JAK/STAT3 Pathways: The Anti-Angiogenic Efficacy of Thienopyridine Derivative LCB03-0110

The study focuses on the identification and evaluation of a compound, LCB03-0110, that exhibits potent inhibition of angiogenesis, a process critical for tumor growth and metastasis. This compound targets key signaling pathways involving Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) and the Janus kinase (JAK)/Signal Transducer and Activator of Transcription 3 (STAT3) signaling.

LCB03-0110 was found to inhibit VEGFR-2, JAK/STAT3 signaling in both primary cultured human endothelial cells and cancer cells. The compound's mechanism of action was elucidated through in vitro kinase assays and molecular modeling, revealing that it binds preferentially at the ATP-binding site of VEGFR-2, c-SRC, and TIE-2 kinases, thereby inhibiting their activity.

The compound effectively suppressed hypoxia-induced HIF/STAT3 and signaling pathways triggered by EGF or angiopoietin. It also reduced VEGF-induced endothelial cell proliferation, viability, migration, and capillary-like tube formation. Furthermore, LCB03-0110 demonstrated the ability to inhibit endothelial cell sprouting in the rat aorta and new blood vessel formation in the mouse Matrigel plug assay.

In addition to its effects on angiogenesis, LCB03-0110 also suppressed pulmonary metastasis and tumor xenograft growth in mice. These findings indicate that LCB03-0110 is a promising candidate for the development of a small molecule therapeutic that can block angiogenesis driven by the aberrant activation of VEGFR-2 and JAK/STAT3 signaling pathways.